Novel steroid payloads, steroid linkers, ADCs containing same, and uses thereof

Abstract

The present invention provides novel glucocorticosteroids, glucocorticosteroid linkers, and antibody drug conjugates (ADCs) comprising antibodies or antibody fragments that bind to antigens expressed on immune cells, optionally antigens expressed on human immune cells. In some cases, the ADCs comprise anti-human VISTA (V-region immunoglobulin-containing inhibitor of T-cell activation (1)) antibodies or anti-VISTA antigen-binding antibody fragments that bind to VISTA-expressing cells at physiological pH with a short serum half-life (≈24-72 hours or 24-48 hours or 12-24 hours or less in human VISTA knock-in rodents, or (≈1-3.5 days or less in humans or non-human primates). In some cases, these ADCs have a rapid onset of action and are highly ingested by large numbers of immune cells where they are cleaved releasing large amounts of active steroid payload. The ADCs are effectively internalized and therefore effective for a long period of time. The invention also relates to the use of such ADCs and novel steroids for the treatment of autoimmune, allergic and inflammatory conditions. The invention further relates to methods for using such ADCs to reduce the deleterious side effects and / or improve the efficacy of glucocorticoid receptor agonists by selectively delivering these anti-inflammatory agents to target immune cells, such as monocytes, neutrophils, B cells, T cells, Tregs, eosinophils, NK cells, macrophages, myeloid cells, in particular myeloid cells, thereby reducing potential toxicity to non-target cells.

Description

[Technical Field]

[0001] The present invention relates to novel glucocorticosteroids, glucocorticosteroid linkers, and antibody-drug conjugates (ADCs) comprising antibodies or antibody fragments that bind to antigens expressed on immune cells, typically human immune cells. In some embodiments, the ADCs comprise anti-human VISTA (V-region immunoglobulin-containing inhibitor of T-cell activation (1)) antibodies or anti-VISTA antigen-binding antibody fragments, e.g., those with short serum half-lives (approximately 24-27 hours or less in human VISTA knock-in rodents). The subject ADCs have rapid onset of action and are long-lasting because they are highly effectively internalized by immune cells, where they are cleaved to release a large amount of active steroid payload. The present invention also relates to the use of such ADCs and novel steroids for the treatment of autoimmune, allergic, inflammatory, and cancer conditions, particularly acute and chronic autoimmune, allergic, and inflammatory conditions. The invention further relates to methods for using such ADCs to reduce the deleterious side effects and / or improve the efficacy of glucocorticoids by selectively delivering these anti-inflammatory agents to target immune cells, typically human immune cells, optionally any of monocytes, neutrophils, T cells, Tregs, eosinophils, B cells, NK cells, etc., particularly myeloid cells, or other immune cells involved in the pathology of the autoimmune, allergic, inflammatory, or cancerous condition being treated, thereby reducing potential toxicity to non-target cells. [Background technology]

[0002] VISTA is an NCR ligand whose closest phylogenetic relative is PD-L1. VISTA shares homology with PD-L1 but displays a unique expression pattern that is restricted to the hematopoietic compartment. Specifically, VISTA binds CD11b high It is constitutively and highly expressed on myeloid cells and CD4 + and CD8 +It is expressed at lower levels on T cells. Like PD-L1, VISTA is a ligand that largely suppresses immunity, and like PD-L1, blocking VISTA allows for the development of therapeutic immunity against cancer in preclinical tumor models. Blocking VISTA suppresses immunity, particularly CD8 + and CD4 + Treatment with a soluble Ig fusion protein (VISTA-Ig) of the extracellular domain of VISTA has been shown to suppress immunity and prevent the progression of multiple mouse models of autoimmune disease, while improving T cell-mediated immunity. Based on the foregoing, the use of antagonistic anti-VISTA antibodies to promote T cell immunity and treat conditions where this is beneficial, such as cancer and infectious diseases, has been reported. Conversely, the use of agonistic anti-VISTA antibodies to inhibit T cell immunity and treat conditions where this is therapeutically beneficial, such as autoimmune, allergic, and inflammatory conditions, has been reported. Unfortunately, some anti-VISTA antibodies, including those used in human clinical trials, possess very short serum half-lives, which are generally undesirable in the context of treating chronic conditions such as cancer or autoimmunity, as they require very frequent administration, which is both inconvenient and ineffective for patients. In addition, the potential use of anti-VISTA antibodies and VISTA fusion proteins to deliver payloads, such as chemotherapeutic agents, to cancer cells or tumor sites has been proposed.

[0003] Synthetic glucocorticoid receptor agonists (e.g., dexamethasone, prednisolone, budesonide, beclomethasone, betamethasone, cortisol, cortisone acetate, 16-alpha-hydroxyprednisolone, dexamethasone, difluorasone, flumethasone, flunisolide, fluocinolone acetonide, fluticasone propionate, ciclesonide, methylprednisolone, prednisone, prednisolone, mometasone, triamcinolone acetonide, etc.) are a potent class of small molecules used to treat inflammation and related disorders. These compounds are highly effective in inhibiting inflammation associated with different conditions, such as autoimmune, allergic, and inflammatory disorders, cancer, and infectious diseases; however, their usefulness in the chronic treatment of inflammatory, allergic, and autoimmune diseases is limited due to their severe side effects.

[0004] Based on the foregoing, several approaches have been explored to preserve the anti-inflammatory effects of synthetic glucocorticoids while eliminating unwanted toxicity (Rosen, J and Miner, JN Endocrine Reviews 26:452-64 (2005)). In particular, antibody-drug conjugates (ADCs) have been developed, in which such compounds are conjugated to antibodies that target antigens expressed by immune cells, including CD40, CD163, CD74, PRLR, and TNF. Nevertheless, in the field of autoimmune, allergic, and inflammatory diseases, there remains a need for improved anti-inflammatory, autoimmune, and allergy therapies, as well as the development of improved anti-inflammatory, autoimmune, and allergy therapeutics that have, for example, improved efficacy, prolonged efficacy, and / or reduced side effects compared to existing therapeutics for the treatment of such conditions. Summary of the Invention

[0005] It is an object of the present invention to provide therapeutic agents for treating or preventing inflammation and related disorders by providing novel steroids, steroid linkers, and ADCs comprising VISTA, an antibody or antibody fragment that targets an antigen expressed by immune cells, typically human immune cells, in some embodiments, where the antibody or antibody fragment is an anti-human VISTA antibody or anti-human VISTA antibody fragment that binds to VISTA-expressing cells at physiological pH.

[0006] It is a specific object of the present invention to provide novel antibody drug conjugates (ADCs) comprising an anti-VISTA antibody or antibody fragment, as disclosed herein, conjugated to a glucocorticoid receptor agonist or glucocorticoid receptor agonist linker, that possess a very short serum half-life at physiological conditions (≈pH 7.5), defined herein as 1-72 hours, 1-32 hours, 1-16 hours, 1-8 hours, 1-4 hours, or 1-2 hours in human VISTA knock-in rodents, or ≈3-4 days or less in cynomolgus monkeys.

[0007] As demonstrated below, the subject ADCs possess a unique combination of advantages over previous ADCs for targeting and directing the internalization of anti-inflammatory agents, particularly steroids, into immune cells due to the novel properties of the steroid linker therein, which provides for rapid internalization and release of large amounts of active payload upon internalization by immune cells.

[0008] The subject ADCs also have a reduced tendency to aggregate compared to previous ADCs containing glucocorticosteroids, thereby providing a high drug-to-antibody ratio (DAR).

[0009] Additionally, the subject ADCs provide increased potency even at lower DARs because they are more effectively internalized and release a more active glucocorticosteroid payload within target immune cells compared to previous ADCs containing glucocorticosteroids.

[0010] Also, in some embodiments, the subject ADCs possess the combined benefits of a steroid linker payload and an anti-VISTA antibody or antibody fragment disclosed herein, particularly one that binds to VISTA-expressing immune cells at physiological pH and possesses a very short pK. In particular, these ADCs bind to VISTA-expressing immune cells, e.g., at very high densities, and, despite their very short PK, are effective (elicit anti-inflammatory activity) for extended periods of time (i.e., possess a PD much longer than their pK), and are therefore well suited to treat chronic inflammatory, or autoimmune or allergic diseases where long-term and repeated administration is therapeutically justified.

[0011] Additionally, subject ADCs comprising anti-VISTA antibodies or antibody fragments target a broad range of immune cells, including activated and resting T cells, Tregs, CD4 T cells, CD8 T cells, neutrophils, myeloid cells, monocytes, macrophages, eosinophils, dendritic cells, NK cells, and endothelial cells; therefore, such ADCs can be used to treat inflammatory, autoimmune, or allergic diseases that involve any or all of these types of immune cells. Alternatively, however, subject ADCs can comprise antibodies or antibody fragments that bind to other immune cell antigens, preferably antibodies or antibody fragments that effectively internalize target immune cells.

[0012] The subject ADCs have a rapid onset of efficacy and can therefore be used to treat acute illnesses. In the case of VISTA antibody-containing ADCs, these ADCs do not bind to B cells and therefore should not be immunosuppressive like free steroids.

[0013] Additionally, in the case of VISTA antibody-containing ADCs, the subject ADCs act on Tregs, which are key immune cells involved in steroid efficacy, and act on both resting and myeloid cells, monocytes, eosinophils, Tregs, CD8 T cells, CD4 T cells, immune cells, etc., and as a result are active (eliciting anti-inflammatory activity) in both active and remission phases of inflammatory and autoimmune conditions.

[0014] Additionally, in the case of VISTA antibody-containing ADCs, the subject ADCs act on neutrophils, immune cells that are essential in acute inflammation.

[0015] Additionally, in the case of VISTA antibody-containing ADCs, due to the high VISTA cell surface turnover, the subject ADCs are very rapidly and constitutively internalized by immune cells.

[0016] Furthermore, in the case of VISTA antibody-containing ADCs, the subject ADCs should possess very short half-lives (PK) and selectively target immune cells, and therefore should not be prone to non-target cell-related toxicity and undesirable peripheral steroid exposure (low non-specific loss effects).

[0017] Additionally, in the case of some VISTA antibody-containing ADCs according to the present invention, the biological activity (anti-inflammatory effect) of the subject ADCs is entirely attributable to the anti-inflammatory payload (steroid), as the anti-VISTA antibody possesses silent IgG therein that does not induce immunological function (there is no blockade of any VISTA biology).

[0018] Novel glucocorticoid agonist compounds having the following structure of formula (I): [ka] X is selected from phenyl, spiro[3.3]heptane, 3-6 membered heterocycle, cycloalkyl, spiroalkyl, spiroheterocycloalkyl, bicyclic alkyl, heterobicyclic alkyl, [1.1.1]bicyclopentane, bicyclo[2.2.2]octane, adamantane, and cubane, each of which can be independently substituted with 1-4 heteroatoms selected from F, Cl, Br, I, N, S, and O, and each of whose ring structures can include at least one skeletal heteroatom selected from N, S, and O, and optionally further substituted with 1-4 C1-3 alkyl or C1-3 perfluoroalkyl; Z is selected from phenyl, spiro[3.3]heptane, 3-6 membered heterocycle, cycloalkyl, spiroalkyl, spiroheterocycloalkyl, bicyclic alkyl, heterobicyclic alkyl, [1.1.1]bicyclopentane, bicyclo[2.2.2]octane, adamantane, and cubane, each of which can be independently substituted with 1-4 heteroatoms selected from F, Cl, Br, I, N, S, and O, and each of whose ring structures can include at least one skeletal heteroatom selected from N, S, and O, and optionally further substituted with 1-4 C1-3 alkyl or C1-3 perfluoroalkyl; Y is selected from CHR, O, S, and NR; E is selected from CH and O; G is selected from CH and N; Furthermore, when G is CH and X is phenyl, Z is not phenyl, the bond of G to X may optionally be selected from C alkyl and ethylene oxide, each of which may be independently substituted with 1-4 heteroatoms selected from N, S, and O, and optionally further substituted with 1-4 C alkyl; the bond of X to Z may occupy any available position on X and Z; The substituent NR1R2 may occupy any available position on Z; R1 is selected from H, linear or branched alkyl of 1 to 8 carbons, aryl, and heteroaryl groups, and the aryl and heteroaryl groups can be substituted with functional groups selected from alkyl, haloalkyl, halogen, biphenyl, nitro, nitrile, -OH, -O-alkyl, -NH2, alkylamino, dialkylamino, thiol, thioalkyl, guanidine, urea, carboxylic acid, alkoxyl, carboxamide, carboxylic acid ester, alkyl-C(O)O-, alkylamino-C(O)-, and dialkylaminoC(O)-; When R1 is H, R2 can be selected from H, linear or branched alkyl of 1 to 8 carbons, aryl, and heteroaryl groups, and the aryl and heteroaryl groups can be substituted with functional groups selected from alkyl, haloalkyl, halogen, biphenyl, nitro, nitrile, -OH, -O-alkyl, -NH2, alkylamino, dialkylamino, thiol, thioalkyl, guanidine, urea, carboxylic acid, alkoxyl, carboxamide, carboxylic acid ester, alkyl-C(O)O-, alkylamino-C(O)-, and dialkylaminoC(O)-; When R1 is H, a linear or branched alkyl of 1 to 8 carbons, or a heteroaryl, R2 is [(C=O)CH(W)NH]m-[C=O]-[V]kJ, C=O)OCH2-p-aminophenyl-NVJ, (C=O)OCH2-p-aminophenyl-N-[(C=O)CH(W)NH]m-[C=O]-[V]kJ, and [V]-(C=O)OCH-p-aminophenyl-N—[(C=O)CH(W)NH]-[C=O]-J; wherein m=1 to 6, k=0 to 1, and each occurrence of W may be independently selected from H, [(CH)R] where n=1 to 4, a branched alkyl chain terminating in R, and a linear or branched polyethylene oxide group containing 1 to 13 units; R3 is selected from H, methyl, ethyl, isopropyl, OH, O-alkyl, NH, NH-alkyl, N-dialkyl, SH, S-alkyl, guanidine, urea, carboxylic acid, carboxamide, carboxylic acid ester, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, wherein the aryl and heteroaryl substituents may be selected from alkyl, haloalkyl, halogen, biphenyl, nitro, nitrile, —OH, —O-alkyl, —NH, alkylamino, dialkylamino, thiol, thioalkyl, guanidine, urea, carboxylic acid, alkoxyl, carboxamide, carboxylic acid ester, alkyl-C(O)O—, alkylamino-C(O)—, and dialkylaminoC(O)—; V is an alkyl chain of 1 to 8 carbons, a linear or branched polyethylene oxide group containing 1 to 13 units, a linear or branched alkyl group containing 1 to 8 carbons, -O-alkyl, carboxylic acid, carboxamide, carboxylic acid ester, alkyl-C(O)O-, alkylamino-C(O)-, dialkylamino-C(O)-, a sequence of 1 to 3 amino acids, each amino acid independently selected from Glu, Gly, Asn, Asp, Gln, Leu, Lys, Ala, βAla, Phe, Val, and Cit. and a heteroaryl group, wherein the aryl and heteroaryl groups may be substituted with a functional group selected from alkyl, haloalkyl, halogen, biphenyl, nitro, nitrile, -OH, -NH2, alkylamino, dialkylamino, thiol, thioalkyl, guanidine, urea, carboxylic acid, alkoxyl, carboxamide, carboxylic acid ester, alkyl-C(O)O-, alkylamino-C(O)-, and dialkylaminoC(O)-; J is -NH2, N3, thio, cyclooctyne, -OH, -CO2H, transcyclooctene, alkynyl, propargyl, [ka] is a reactive group selected from wherein R32 is selected from Cl, Br, F, mesylate, and tosylate; R33 is selected from Cl, Br, I, F, OH, —ON-succinimidyl, —O-(4-nitrophenyl), —O-pentafluorophenyl, or —O-tetrafluorophenyl; and R34 is H, Me, tetrazine-H, and tetrazine-Me; R5 is -CH2OH, -CH2SH, -CH2Cl, -SCH2Cl, -SCH2F, -SCH2CF3, hydroxy, -OCH2CN, -OCH2Cl, -OCH2F, -OCH3, -OCH2CH3, -SCH2CN, and [ka] is selected from the group consisting of R6 and R7 are independently selected from hydrogen and C1-10 alkyl; Q is H, [ka] R8 can be C(O)R8, where R8 is a straight or branched alkyl of 1 to 8 carbons, or (C=O)NR4CHnNR4(C=O)OCH2-(V)nJ, where n=1-4 and R4=H, alkyl or branched alkyl, or P(O)OR4; A1 and A2 are independently selected from H and F; It is a specific object of this invention to provide novel glucocorticoid agonist compounds, of which all possible stereoisomers are claimed unless otherwise specified.

[0019] It is a specific object of the present invention to provide a glucocorticoid agonist compound as described above, wherein X and Z are independently selected from phenyl, spiro[3.3]heptane, [1.1.1]bicyclopentane, and bicyclo[2.2.2]octane; Y is selected from CH and O; and the sequence of W is independently selected from CHCHCOH and H; and further, when G is CH and X is phenyl, Z is not phenyl.

[0020] It is a specific object of the present invention to provide a glucocorticoid agonist compound as described above, which is selected from any of the glucocorticoid agonist compounds disclosed in Example 3, excluding INX J and INX L, or selected from those shown in Figure 11.

[0021] It is a specific object of the present invention to provide a glucocorticoid agonist compound as described above, selected from INX-steroid payload, INX-steroid linker, and INX-antibody drug conjugate (ADC) compounds, excluding INX J and INX L.

[0022] below: [ka] It is a specific object of the present invention to provide a glucocorticoid agonist compound as described above, which is selected from:

[0023] It is a specific object of the present invention to provide glucocorticoid agonist compounds as described above that are directly or indirectly attached to at least one cleavable or non-cleavable peptide and / or non-peptide linker (i.e., a "steroid-linker payload").

[0024] A compound (steroid-linker payload) comprising at least one cleavable or non-cleavable linker (“L”), optionally “Q” which is a “heterobifunctional” or “heterotrifunctional” chemical moiety used to connect the linker in the compound to an antibody or antibody fragment, and at least one anti-inflammatory agent (“AI”), wherein “AI” has the following structure: QL-AI or AI-LQ It is a specific object of the present invention to provide a compound (steroid-linker payload) which is any of the foregoing glucocorticoid agonist compounds which can be represented by:

[0025] It is a specific object of the present invention to provide a steroid-linker payload as described above, wherein the linker is selected from those disclosed herein.

[0026] PAB and / or amino acids or peptides, optionally 1 to 12 amino acids, further optionally dipeptides, tripeptides, quattrapeptides, pentapeptides, further optionally Gly, Asn, Asp, Gln, Leu, Lys, Ala, Phe, Cit, Val, Val-Cit, Val-Ala, Val-Gly, Val-Gln, Ala-Val, Cit-Cit, Lys-Val-Cit, Asp-Val-Ala, Ala-Ala-Asn, Asp-Val-Ala, Al It is a specific object of the present invention to provide a steroid-linker payload as defined in any of the foregoing, comprising at least one cleavable or non-cleavable linker selected from a-Val-Cit, Ala-Asn-Val, βAla-Leu-Ala-Leu, Lys-Val-Ala, Val-Leu-Lys, Asp-Val-Cit, Val-Ala-Val, and Ala-Ala-Asn, or optionally at least one of GlcA, PAB, and Glu-Gly.

[0027] It is a specific object of the present invention to provide a steroid-linker payload as described above, which comprises at least one cleavable and / or sacrificial linker attached directly or indirectly to a glucocorticoid agonist steroid compound.

[0028] It is a specific object of the present invention to provide a glucocorticoid agonist compound or steroid-linker payload compound as described in any of the foregoing, or an ADC containing the same, selected from any of the glucocorticoid agonist compounds or steroid-linker payload compounds disclosed in the Examples, e.g., Example 3, excluding INX J and INX L, and any of the compounds depicted in Figures 118A-O.

[0029] below: (i) INX-SM-3-GluGly-alkoxyamine, INX-SM-4-GluGly-alkoxyamine, INX-SM-53-GluGly-alkoxyamine, INX-SM-54-GluGly-alkoxyamine, INX-SM-56-GluGly-alkoxyamine, INX-SM-98-GluGly-alkoxyamine, INX-SM-6-GluGly-alkoxyamine, INX-SM-2-GluGly-alkoxyamine, INX-SM-57-GluGly-alkoxyamine, INX-SM-31-GluGly-alkoxyamine, INX-SM-32-GluGly-alkoxyamine, INX-SM-10-GluGly-alkoxyamine, INX-SM-40-GluGly-alkoxyamine a glucocorticoid agonist (payload) linker conjugate in which Glu-Gly is replaced with a different cleavable peptide linker and another INX or INX-SM payload is replaced with an INX-SM payload contained therein, optionally selected from those of Figures 118A-O; or (ii) INX-SM-53-GluGly-bromoacetyl, INX-SM-3-GluGly-bromoacetyl, INX-SM-54-GluGly-bromoacetyl, INX-SM-1-GluGly-bromoacetyl, INX-SM-4-GluGly-bromoacetyl, INX-SM-2-GluGly-bromoacetyl, INX-SM-47-GluGly-bromoacetyl, INX-SM-7-GluGly-bromoacetyl, INX-SM-8-GluGly-bromoacetyl, INX-SM-56-GluGly-bromoacetyl, INX-SM-32-GluGly-bromoacetyl, INX-SM-6-GluGly-bromoacetyl, INX-SM-10-GluGly-bromoacetyl, INX-SM-33-GluGly-bromoacetyl Glucocorticoid agonist (payload) linker conjugates in which acetyl, INX-SM-31-GluGly-bromoacetyl, INX-SM-35-GluGly-bromoacetyl, INX-SM-9-GluGly-bromoacetyl, INX-SM-28-GluGly-bromoacetyl, INX-SM-27-GluGly-bromoacetyl, INX-SM-34-GluGly-bromoacetyl, INX-SM-35-GluGly-bromoacetyl, INX-SM-40-GluGly-bromoacetyl, or Glu-Gly is replaced with a different cleavable peptide linker and another INX or INX-SM payload is replaced with an INX-SM payload contained therein, optionally selected from those of Figures 118A-O; (iii) INX-SM-53-GluGly-dibenzocyclooctyne, INX-SM-1-GluGly-dibenzocyclooctyne, INX-SM-4-GluGly-dibenzocyclooctyne, INX-SM-54-GluGly-dibenzocyclooctyne, INX-SM-7-GluGly-dibenzocyclooctyne, INX-SM-8-GluGly-dibenzocyclooctyne, INX-SM-2-GluGly-dibenzocyclooctyne, INX-SM-57-GluGly-dibenzocyclooctyne, INX-SM-40-GluGly-dibenzocyclooctyne, INX-SM-34-GluGly-dibenzocyclooctyne, INX-SM-28-GluGly-dibenzocyclooctyne, INX-SM-27-GluGly-dibenzocyclooctyne, INX-SM-35-GluGly-dibenzocyclooctyne or a glucocorticoid agonist (payload) linker conjugate in which GluGly is replaced with a different cleavable peptide linker, and another INX or INX-SM payload is replaced with an INX-SM payload contained therein, optionally selected from those of Figures 118A-O; or (iv) INX-SM-1-GluGly-NHS ester, INX-SM-31-GluGly-NHS ester, INX-SM-32-GluGly-NHS ester, INX-SM-33-GluGly-NHS ester, INX-SM-53-GluGly-NHS ester, INX-SM-7-GluGly-NHS ester, INX-SM-8-GluGly-NHS ester, INX-SM-2-GluGly-NHS ester, INX-SM-56-GluGly-NHS ester, INX-SM-6-GluGly-NHS ester, INX-SM-54-GluGly-NHS ester, INX-SM-4-GluGly-NHS ester, INX-SM-53-GluGly-NHS ester, INX-SM-3-GluGly-NHS ester, INX-SM- Glucocorticoid agonist (payload) linker conjugates in which 9-GluGly-NHS ester, INX-SM-40-GluGly-NHS ester, INX-SM-34-GluGly-NHS ester, INX-SM-28-GluGly-NHS ester, INX-SM-34-GluGly-NHS ester, INX-SM-28-GluGly-NHS ester, INX-SM-27-GluGly-NHS ester, INX-SM-35-GluGly-NHS ester, INX-SM-10-GluGly-NHS ester, or GluGly is replaced with a different cleavable peptide linker and another INX or INX-SM payload is replaced with an INX-SM payload contained therein, optionally selected from those of Figures 118A-O; (v) INX-SM-1-GluGly-maleimide, INX-SM-3-GluGly-maleimide, INX-SM-4-GluGly-maleimide, INX-SM-8-GluGly-maleimide, INX-SM-2-GluGly-maleimide, INX-SM-7-GluGly-maleimide, INX-SM-56-GluGly-maleimide, INX-SM-6-GluGly-maleimide, INX-SM-54-GluGly-maleimide, INX-SM-53-GluGly-maleimide, INX-SM-33-GluGly-maleimide, INX-SM-35-GluGly-maleimide, INX-SM-40-GluGly-maleimide, INX-SM-34-GluGly-maleimide, INX - a glucocorticoid agonist (payload) linker conjugate in which SM-28-GluGly-maleimide, INX-SM-27-GluGly-maleimide, INX-SM-35-GluGly-maleimide, INX-SM-9-GluGly-maleimide, INX-SM-10-GluGly-maleimide, INX-SM-31-GluGly-maleimide, INX-SM-32-GluGly-maleimide, INX-SM-57-GluGly-maleimide, or GluGly is replaced with a different cleavable peptide linker and another INX or INX-SM payload is replaced with an INX-SM payload contained therein, optionally selected from those of Figures 118A-O; or (vi) INX-SM-3-GluGly-tetrazine, INX-SM-53-GluGly-tetrazine, INX-SM-1-GluGly-tetrazine, INX-SM-54-GluGly-tetrazine, INX-SM-6-GluGly-tetrazine, INX-SM-56-GluGly-tetrazine, INX-SM-4-GluGly-tetrazine, INX-SM-10-GluGly-tetrazine, INX-SM-31-GluGly-tetrazine, INX-SM-32-GluGly-tetrazine, INX-SM-33-GluGly-tetrazine, INX-SM-7-GluGly-tetrazine, INX-SM-8-GluGly-tetrazine, INX-SM-9-GluGly-tetrazine a glucocorticoid agonist (payload) linker conjugate in which ly-tetrazine, INX-SM-27-GluGly-tetrazine, INX-SM-35-GluGly-tetrazine, INX-SM-2-GluGly-tetrazine, INX-SM-40-GluGly-tetrazine, INX-SM-34-GluGly-tetrazine, INX-SM-28-GluGly-tetrazine, INX-SM-27-GluGly-tetrazine, or GluGly is replaced with a different cleavable peptide linker and another INX or INX-SM payload is replaced with an INX-SM payload contained therein, optionally selected from those of Figures 118A-O; or (vii) INX-SM-6-GluGly-amine, INX-SM-54-GluGly-amine, INX-SM-4-GluGly-amine, INX-SM-53-GluGly-amine, INX-SM-2-GluGly-amine, INX-SM-56-GluGly-amine, INX-SM-57-GluGly-amine, INX-SM-35-GluGly-amine, INX-SM-27-GluGly-amine, INX-SM-40-GluGly-amine, INX-SM-34-GluGly-amine, INX-SM-28-GluGly-amine, INX-SM-35-GluGly-amine, INX-SM-9-GluGly-amine, INX-S a glucocorticoid agonist (payload) linker conjugate in which M-10-GluGly-amine, INX-SM-31-GluGly-amine, INX-SM-32-GluGly-amine, INX-SM-33-GluGly-amine, INX-SM-7-GluGly-amine, INX-SM-8-GluGly-amine, INX-SM-1-GluGly-amine, INX-SM-3-GluGly-amine, or GluGly is replaced with a different cleavable peptide linker and another INX or INX-SM payload is replaced for the INX-SM payload contained therein, optionally selected from those of Figures 118A-O; or (viii) INX-SM-53-PAB-GluGly-alkoxyamine, INX-SM-1-PAB-GluGly-alkoxyamine, INX-SM-3-PAB-GluGly-alkoxyamine, INX-SM-2-PAB-GluGly-alkoxyamine, INX-SM-56-PAB-GluGly-alkoxyamine, INX-SM-35-PAB-GluGly-alkoxyamine, INX-SM-25-PAB-GluGly-alkoxyamine Alkoxyamine, INX-SM-27-PAB-GluGly-alkoxyamine, INX-SM-35-PAB-GluGly-alkoxyamine, INX-SM-9-PAB-GluGly-alkoxyamine, INX-SM-10-PAB-GluGly-alkoxyamine, INX-SM-31-PAB-GluGly-alkoxyamine, INX-SM-32-PAB-GluGly-alkoxyamine, INX-SM-33-PAB-GluGly y-alkoxyamine, INX-SM-57-PAB-GluGly-alkoxyamine, INX-SM-7-PAB-GluGly-alkoxyamine, INX-SM-8-PAB-GluGly-alkoxyamine, INX-SM-6-PAB-GluGly-alkoxyamine, INX-SM-54-PAB-GluGly-alkoxyamine, INX-SM-4-PAB-GluGly-alkoxyamine, INX-SM-40-PAB-GluGly-alkoxyamine, INX-SM-34-PAB-GluGly-alkoxyamine, or another glucocorticoid agonist (payload) linker conjugate in which GluGly and / or PAB are replaced with a different cleavable peptide or non-peptide linker and another INX or INX-SM payload is replaced with an INX-SM payload contained therein, optionally selected from those of Figures 118A-O; or (ix) INX-SM-1-PAB-GluGly-bromoacetyl, INX-SM-3-PAB-GluGly-bromoacetyl, INX-SM-2-PAB-GluGly-bromoacetyl, INX-SM-7-PAB-GluGly-bromoacetyl, INX-SM-8-PAB-GluGly-bromoacetyl, INX-SM-40-PAB-GluGly-bromoacetyl, INX-SM-56-PAB-Glu Gly-Bromoacetyl, INX-SM-6-PAB-GluGly-Bromoacetyl, INX-SM-154PAB-GluGly-Bromoacetyl, INX-SM-4-PAB-GluGly-Bromoacetyl, INX-SM-33-PAB-GluGly-Bromoacetyl, INX-PAB-GluGly-Bromoacetyl, INX-SM-32-PAB-GluGly-Bromoacetyl, INX-SM-10-PA B-GluGly-Bromoacetyl, INX-SM-34-PAB-GluGly-Bromoacetyl, INX-SM-31-PAB-GluGly-Bromoacetyl, INX-SM-9-PAB-GluGly-Bromoacetyl, INX-SM-28-PAB-GluGly-Bromoacetyl, INX-SM-27-PAB-GluGly-Bromoacetyl, INX-SM-35-PAB-GluGly-Bromoacetyl, INX-SM-53-PAB-GluGly-Bromoacetyl, or another glucocorticoid agonist (payload) linker conjugate in which GluGly and / or PAB are replaced with a different cleavable peptide or non-peptide linker and another INX or INX-SM payload is replaced with an INX-SM payload contained therein, optionally selected from those of Figures 118A-O; (x) INX-SM-6-PAB-GluGly-dibenzocyclooctyne, INX-SM-54-PAB-GluGly-dibenzocyclooctyne, INX-SM-4-PAB-GluGly-dibenzocyclooctyne, INX-SM-53-PAB-GluGly-dibenzocyclooctyne, INX-SM-1-PAB-GluGly-dibenzocyclooctyne, INX-SM-7-PAB-GluGly-dibenzocyclooctyne, INX-SM-8-PAB-GluGly-dibenzocyclooctyne, INX-SM-2-PAB-GluGly-dibenzocyclooctyne, INX -SM-56-PAB-GluGly-dibenzocyclooctyne, INX-SM-57-PAB-GluGly-dibenzocyclooctyne, INX-SM-33-PAB-GluGly-dibenzocyclooctyne, INX-SM-32-PAB-GluGly-dibenzocyclooctyne, INX-SM-31-PAB-GluGly-dibenzocyclooctyne, INX-SM-3-PAB-GluGly-dibenzocyclooctyne, IN X-SM-9-PAB-GluGly-dibenzocyclooctyne, INX-SM-27-PAB-GluGly-dibenzocyclooctyne, INX-SM-35-PAB-GluGly-dibenzocyclooctyne, INX-SM-34-PAB-GluGly-dibenzocyclooctyne, INX-SM-28-PAB-GluGly-dibenzocyclooctyne, INX-SM-40-PAB-GluGly-dibenzocyclooctyne, INX-SM-10-PAB-GluGly-dibenzocyclooctyne, or another glucocorticoid agonist (payload) linker conjugate in which GluGly and / or PAB are replaced with a different cleavable peptide or non-peptide linker and another INX or INX-SM payload is replaced with an INX-SM payload contained therein, optionally selected from those of Figures 118A-O; or (xi) INX-SM-56-PAB-GluGly-NHS ester, INX-SM-54-PAB-GluGly-NHS ester, INX-SM-4-PAB-GluGly-NHS ester, INX-SM-53-PAB-GluGly-NHS ester, INX-SM-1-PAB-GluGly-NHS ester, INX-SM-3-PAB-GluGly-NHS ester, INX-SM-33-PAB-GluGly-NHS ester, INX-SM-57-PAB-GluGly-NHS ester, INX-SM-7-PAB-GluGly-NHS ester, INX-SM-8-PAB-GluGly-NHS ester, INX-SM-27-PAB-GluGly-NHS ester, INX-SM-35-PAB-GluGly-NHS ester, INX-SM-9-PAB-GluGly-NHS ester ester, INX-SM-10-PAB-GluGly-NHS ester, INX-SM-31-PAB-GluGly-NHS ester, INX-SM-32-PAB-GluGly-NHS ester, INX-SM-40-PAB-GluGly-NHS ester, INX-SM-34-PAB-GluGly-NHS ester, INX-SM-28-PAB-GluGly-NHS ester, INX-SM-2-PAB-GluGly-NHS ester, or another glucocorticoid agonist (payload) linker conjugate in which GluGly and / or PAB are replaced with a different cleavable peptide or non-peptide linker and another INX or INX-SM payload is replaced with an INX-SM payload contained therein, optionally selected from those of Figures 118A-O; or (xii) INX-SM-1-PAB-GluGly-maleimide, INX-SM-53-PAB-GluGly-maleimide, INX-SM-5-PAB-GluGly-maleimide, INX-SM-2-PAB-GluGly-maleimide, INX-SM-8-PAB-GluGly-maleimide, INX-SM-56-PAB-GluGly-maleimide, INX-SM-54-PAB-GluGly y-Maleimide, INX-SM-4-PAB-GluGly-maleimide, INX-SM-57-PAB-GluGly-maleimide, INX-SM-7-PAB-GluGly-maleimide, INX-SM-32-PAB-GluGly-maleimide, INX-SM-31-PAB-GluGly-maleimide, INX-SM-53-PAB-GluGly-maleimide, INX-SM-3-PAB-G or another glucocorticoid agonist (payload) linker conjugate in which GluGly and / or PAB are replaced with a different cleavable peptide or non-peptide linker and another INX or INX-SM payload is replaced with an INX-SM payload contained therein, optionally selected from those of Figures 118A-O; or (xiii) INX-SM-6-PAB-GluGly-tetrazine, INX-SM-54-PAB-GluGly-tetrazine, INX-SM-4-PAB-GluGly-tetrazine, INX-SM-53-PAB-GluGly-tetrazine, INX-SM-1-PAB-GluGly-tetrazine, INX-SM-3-PAB-GluGly-tetrazine, INX-SM-57-PAB-GluGly-tetrazine INX-SM-7-PAB-GluGly-tetrazine, INX-SM-8-PAB-GluGly-tetrazine, INX-SM-2-PAB-GluGly-tetrazine, INX-SM-31-PAB-GluGly-tetrazine, INX-SM-32-PAB-GluGly-tetrazine, INX-SM-33-PAB-GluGly-tetrazine, INX-SM-56-PAB-GluGly-tetrazine, I NX-SM-35-PAB-GluGly-tetrazine, INX-SM-9-PAB-GluGly-tetrazine, INX-SM-40-PAB-GluGly-tetrazine, INX-SM-34-PAB-GluGly-tetrazine, INX-SM-28-PAB-GluGly-tetrazine, INX-SM-27-PAB-GluGly-tetrazine, INX-SM-35-PAB-GluGly-tetrazine, INX-SM-10-PAB-GluGly-tetrazine, or another glucocorticoid agonist (payload) linker conjugate in which GluGly and / or PAB are replaced with a different cleavable peptide or non-peptide linker and another INX or INX-SM payload is replaced with an INX-SM payload contained therein, optionally selected from those of Figures 118A-O; or (xiv) INX-SM-1-PAB-GluGly-amine, INX-SM-3-PAB-GluGly-amine, INX-SM-8-PAB-GluGly-amine, INX-SM-2-PAB-GluGly-amine, INX-SM-56-PAB-GluGly-amine, INX-SM-6-PAB-GluGly-amine, INX-SM-54-PAB-GluGly-amine, INX-SM-4-PAB-GluGly-amine, INX-SM-53-PAB-GluGly-amine, INX-SM-33-PAB-GluGly-amine, INX-SM-53-PAB-GluGly-amine, INX-SM-7-PAB-GluGly-amine, INX-SM-9-PAB-GluGly-amine, INX-SM-35-PAB-GluGly-amine, INX-SM-40 -PAB-GluGly-amine, INX-SM-34-PAB-GluGly-amine, INX-SM-28-PAB-GluGly-amine, INX-SM-27-PAB-GluGly-amine, INX-SM-35-PAB-GluGly-amine, INX-SM-10-PAB-GluGly-amine, INX-SM-31-PAB-GluGly-amine, INX-SM-32-PAB-GluGly-amine, or another glucocorticoid agonist (payload) linker conjugate in which GluGly and / or PAB are replaced with a different cleavable peptide or non-peptide linker and another INX or INX-SM payload is replaced with an INX-SM payload contained therein, optionally selected from those of Figures 118A-O; or (xv) INX-SM-1-PAB-GlcA-alkoxyamine, INX-SM-35-PAB-GlcA-alkoxyamine, INX-SM-9-PAB-GlcA-alkoxyamine, INX-SM-10-PAB-GlcA-alkoxyamine, INX-SM-54-PAB-GlcA-alkoxyamine, INX-SM-31-PAB-GlcA-alkoxyamine, INX-SM-32-PAB-GlcA-alkoxyamine, INX-SM-33-PAB-GlcA-alkoxyamine, INX-SM-57-PAB-GlcA-alkoxyamine, INX-SM-7-PAB-GlcA-alkoxyamine, INX-SM-8-PAB-GlcA-alkoxyamine, INX-SM-2-PAB-GlcA-alkoxyamine, INX-SM-56-PAB-GlcA-alkoxyamine, INX-SM-6-PAB AB-GlcA-alkoxyamine, INX-SM-4-PAB-GlcA-alkoxyamine, INX-SM-53-PAB-GlcA-alkoxyamine, INX-SM-27-PAB-GlcA-alkoxyamine, INX-SM-40-PAB-GlcA-alkoxyamine, INX-SM-34-PAB-GlcA-alkoxyamine, INX-SM-28-PAB-GlcA-alkoxyamine, INX-SM-3-PAB-GlcA-alkoxyamine, or another glucocorticoid agonist (payload) linker conjugate in which GlcA and / or PAB are replaced with a different cleavable peptide or non-peptide linker and another INX or INX-SM payload is replaced with an INX-SM payload contained therein, optionally selected from those of Figures 118A-O; or (xvi) INX-SM-3-PAB-GlcA-bromoacetyl, INX-SM-4-PAB-GlcA-bromoacetyl, INX-SM-56-PAB-GlcA-bromoacetyl, INX-SM-54-PAB-GlcA-bromoacetyl, INX-SM-4-PAB-GlcA-bromoacetyl, INX-SM-53-PAB-GlcA-bromoacetyl, INX-SM-7-PAB-GlcA- Bromoacetyl, INX-SM-8-PAB-GlcA-bromoacetyl, INX-SM-2-PAB-GlcA-bromoacetyl, INX-SM-40-PAB-GlcA-bromoacetyl, INX-SM-57-PAB-GlcA-bromoacetyl, INX-SM-33-PAB-GlcA-bromoacetyl, INX-SM-10-PAB-GlcA-bromoacetyl, INX-SM-34-PAB- or another glucocorticoid agonist (payload) linker conjugate in which GluGly and / or PAB are replaced with a different cleavable peptide or non-peptide linker, and another INX or INX-SM payload is replaced with an INX-SM payload contained therein, optionally selected from those of Figures 118A-O; or (xvii) INX-SM-4-PAB-GlcA-dibenzocyclooctyne, INX-SM-54-PAB-GlcA-dibenzocyclooctyne, INX-SM-1-PAB-GlcA-dibenzocyclooctyne, INX-SM-54-PAB-GlcA-dibenzocyclooctyne, INX-SM-33-PAB-GlcA-dibenzocyclooctyne, INX-SM-57-PAB-GlcA-dibenzocyclooctyne, INX-SM-7-PAB-GlcA-dibenzocyclooctyne INX-SM-8-PAB-GlcA-dibenzocyclooctyne, INX-SM-2-PAB-GlcA-dibenzocyclooctyne, INX-SM-5-PAB-GlcA-dibenzocyclooctyne, INX-SM-6-PAB-GlcA-dibenzocyclooctyne, INX-SM-35-PAB-GlcA-dibenzocyclooctyne, INX-SM-9-PAB-GlcA-dibenzocyclooctyne, INX-SM-10-PAB-GlcA-dibenzocyclooctyne Benzocyclooctyne, INX-SM-31-PAB-GlcA-dibenzocyclooctyne, INX-SM-32-PAB-GlcA-dibenzocyclooctyne, INX-SM-27-PAB-GlcA-dibenzocyclooctyne, INX-SM-35-PAB-GlcA-dibenzocyclooctyne, INX-SM-28-PAB-GlcA-dibenzocyclooctyne, INX-SM-34-PAB-GlcA-dibenzocyclooctyne, INX-SM-40-PAB -GlcA-dibenzocyclooctyne, INX-SM-3-PAB-GlcA-dibenzocyclooctyne, or another glucocorticoid agonist (payload) linker conjugate in which GlcA and / or PAB are replaced with a different cleavable peptide or non-peptide linker and another INX or INX-SM payload is replaced with an INX-SM payload contained therein, optionally selected from those of Figures 118A-O; or (xviii) INX-SM-3-PAB-GlcA-NHS ester, INX-SM-53-PAB-GlcA-NHS ester, INX-SM-4-PAB-GlcA-NHS ester, INX-SM-56-PAB-GlcA-NHS ester, INX-SM-54-PAB-GlcA-NHS ester, INX-SM-8-PAB-GlcA-NHS ester, INX-SM-2-PAB-GlcA-NHS ester, INX-SM-7-PAB-GlcA-NHS ester, INX-SM-57-PAB-GlcA-NHS ester, INX-SM-32-PAB-GlcA-NHS ester, INX-SM-33-PAB-GlcA-NHS ester, INX-SM-31-PAB-GlcA-NHS ester, INX-SM-9-PAB-GlcA-NHS ester , INX-SM-10-PAB-GlcA-NHS ester, INX-SM-35-PAB-GlcA-NHS ester, INX-SM-27-PAB-GlcA-NHS ester, INX-SM-28-PAB-GlcA-NHS ester, INX-SM-40-PAB-GlcA-NHS ester, INX-SM-34-PAB-GlcA-NHS ester, INX-SM-1-PAB-GlcA-NHS ester, or another glucocorticoid agonist (payload) linker conjugate in which GlcA and / or PAB are replaced with a different cleavable peptide or non-peptide linker and another INX or INX-SM payload is replaced with an INX-SM payload contained therein, optionally selected from those of Figures 118A-O; or (xix) INX-SM-3-PAB-GlcA-maleimide, INX-SM-4-PAB-GlcA-maleimide, INX-SM-53-PAB-GlcA-maleimide, INX-SM-31-PAB-GlcA-maleimide, INX-SM-32-PAB-GlcA-maleimide, INX-SM-33-PAB-GlcA-maleimide, INX-SM-53-PAB-GlcA -maleimide, INX-SM-7-PAB-GlcA-maleimide, INX-SM-8-PAB-GlcA-maleimide, INX-SM-2-PAB-GlcA-maleimide, INX-SM-56-PAB-GlcA-maleimide, INX-SM-6-PAB-GlcA-maleimide, INX-SM-54-PAB-GlcA-maleimide, INX-SM-1-PAB-GlcA- maleimide, INX-SM-9-PAB-GlcA-maleimide, INX-SM-35-PAB-GlcA-maleimide, INX-SM-27-PAB-GlcA-maleimide, INX-SM-28-PAB-GlcA-maleimide, INX-SM-34-PAB-GlcA-maleimide, INX-SM-40-PAB-GlcA-maleimide, INX-SM-10-PAB-GlcA-maleimide, or another glucocorticoid agonist (payload) linker conjugate in which GlcA and / or PAB are replaced with a different cleavable peptide or non-peptide linker and another INX or INX-SM payload is replaced with an INX-SM payload contained therein, optionally selected from those of Figures 118A-O; or (xx) INX-SM-33-PAB-GlcA-tetrazine, INX-SM-57-PAB-GlcA-tetrazine, INX-SM-7-PAB-GlcA-tetrazine, INX-SM-8-PAB-GlcA-tetrazine, INX-SM-2-PAB-GlcA-tetrazine, INX-SM-56-PAB-GlcA-tetrazine, INX-SM-6-PAB-GlcA-tetrazine, INX-SM-54-PAB-GlcA-tetrazine, INX-SM-4-PAB-GlcA-tetrazine, INX-SM-9-PAB-GlcA-tetrazine, INX-SM-35-PAB-GlcA-tetrazine, INX-SM-2 7-PAB-GlcA-tetrazine, INX-SM-28-PAB-GlcA-tetrazine, INX-SM-34-PAB-GlcA-tetrazine, INX-SM-40-PAB-GlcA-tetrazine, INX-SM-10-PAB-GlcA-tetrazine, or another glucocorticoid agonist (payload) linker conjugate in which GlcAy and / or PAB are replaced with a different cleavable peptide or non-peptide linker and another INX or INX-SM payload is replaced with an INX-SM payload contained therein, optionally selected from those of Figures 118A-O; or (xxi) INX-SM-1-PAB-GlcA-amine, INX-SM-3-PAB-GlcA-amine, INX-SM-53-PAB-GlcA-amine, INX-SM-6-PAB-GlcA-amine, INX-SM-54-PAB-GlcA-amine, INX-SM-8-PAB-GlcA-amine, INX-SM-2-PAB-GlcA-amine, INX-SM-56-PAB-GlcA-amine, INX-SM-4-PAB-GlcA-amine, INX-SM-35-PAB-GlcA-amine, INX-SM-8-PAB-GlcA-amine, INX-SM-10-PAB-GlcA-amine, INX-SM-31-PAB-GlcA-amine, INX-SM-32-PAB-GlcA-amine, INX-SM-33-PAB -GlcA-amine, INX-SM-57-PAB-GlcA-amine, INX-SM-27-PAB-GlcA-amine, INX-SM-35-PAB-GlcA-amine, INX-SM-34-PAB-GlcA-amine, INX-SM-28-PAB-GlcA-amine, INX-SM-40-PAB-GlcA-amine, INX-SM-7-PAB-GlcA-amine, or another glucocorticoid agonist (payload) linker conjugate in which GlcA and / or PAB are replaced with a different cleavable peptide or non-peptide linker and another INX or INX-SM payload is replaced with an INX-SM payload contained therein, optionally selected from those of Figures 118A-O; or (xxii) Alkoxyamine-GlcA-PAB-DMEDA-INX-SM3, or Alkoxyamine-GlyGlu-PAB-DMEDA-INX-SM3, or other linker payloads comprising the same or different peptide or non-peptide linkers, wherein the linker is attached to the same or different INX steroid via C11-OH; (xxiii) Bromoacetyl-GlcA-PAB-DMEDA-INX-SM3, or Bromoacetyl-GlyGlu-PAB-DMEDA-INX-SM3, or other linker payloads comprising the same or different peptide or non-peptide linkers, wherein the linker is attached to the same or different INX steroid via C11-OH; (xxiv) Dibenzocyclooctyne-GlcA-PAB-DMEDA-INX-SM3, or Dibenzocyclooctyne-GlyGlu-PAB-DMEDA-INX-SM3, or other linker payloads comprising the same or different peptide or non-peptide linkers, wherein the linker is attached to the same or different INX steroid via C11-OH; (xxv) tetrazine-GlcA-PAB-DMEDA-INX-SM3, or tetrazine-GlyGlu-PAB-DMEDA-INX-SM3, or other linker payloads comprising the same or different peptide or non-peptide linkers, wherein the linker is attached to the same or different INX steroid via C11-OH; (xxvi) Alkoxyamine-GlcA-PAB-DMEDA-INX-SM3, or Alkoxyamine-GlyGlu-PAB-DMEDA-INX-SM3, or other linker payloads comprising the same or different INX steroid payloads, wherein the linker is attached to the same or different INX steroid through C17; (xxvii) Bromoacetyl-GlcA-PAB-DMEDA-INX-SM3, or Bromoacetyl-GlyGlu-PAB-DMEDA-INX-SM3, or other linker payloads comprising the same or different INX steroid payloads, wherein the linker is attached to the same or different INX steroid through C17; (xxviii) Maleimido-GlcA-PAB-DMEDA-INX-SM3, or Maleimido-GlyGlu-PAB-DMEDA-INX-SM3, or other linker payloads comprising the same or different INX steroid payloads, wherein the linker is attached to the same or different INX steroid through C17; (xxix) Dibenzocyclooctyne-GlcA-PAB-DMEDA-INX-SM3, or Dibenzocyclooctyne-GlyGlu-PAB-DMEDA-INX-SM3, or other linker payloads comprising the same or different INX steroid payloads, wherein the linker is attached to the same or different INX steroid through C17; (xxx) tetrazine-GlcA-PAB-DMEDA-INX-SM3, or tetrazine-GlyGlu-PAB-DMEDA-INX-SM3, or other linker payloads comprising the same or different INX steroid payloads, wherein the linker is attached to the same or different INX steroid through C17; and (xxxi) It is a specific object of the present invention to provide a glucocorticoid agonist (payload) linker conjugate selected from amine-GlcA-PAB-DMEDA-INX-SM3, or amine-GlyGlu-PAB-DMEDA-INX-SM3, or other linker payloads comprising the same or different linkers, wherein the linker is attached via C17 to the same or different INX steroid payload.

[0030] 13. An antibody drug conjugate (ADC) selected from: (i) Ab-Gly-Glu-PAB-DMEDA-INX-3 or Ab-GlcA-PAB-DMEDA-INX-SM-3 (alkoxyamine + ketone conjugation (C11-OH linkage)), or another ADC containing a different INX-SM payload, in which the INX-SM payload is conjugated to the antibody via alkoxyamine + ketone conjugation and linked to the C11-OH; (ii) Ab-Gly-Glu-PAB-DMEDA-INX-3 or Ab-GlcA-PAB-DMEDA-INX-SM-3 (azide + dibenzocyclooctyne conjugation (C11-OH linkage)), or another ADC containing a different INX-SM payload, in which the INX-SM payload is conjugated to the antibody via azide + dibenzocyclooctyne conjugation and linked to the C11-OH; (iii) another ADC containing a different INX-SM payload, either Ab-Gly-Glu-PAB-DMEDA-INX-3 or Ab-GlcA-PAB-DMEDA-INX-SM-3 (haloacetyl + cysteine ​​conjugation (C11-OH linkage) or the INX-SM payload is conjugated to the antibody via azide + dibenzocyclooctyne conjugation and C11-OH linkage); (iv) another ADC containing a different INX-SM payload, Ab-Gly-Glu-PAB-DMEDA-INX-3 or Ab-GlcA-PAB-DMEDA-INX-SM-3 (maleimide + cysteine ​​conjugation (C11-OH linkage) or the INX-SM payload is conjugated to the antibody via azide + dibenzocyclooctyne conjugation and C11-OH linkage); (v) Ab-Gly-Glu-PAB-DMEDA-INX-3 or Ab-GlcA-PAB-DMEDA-INX-SM-3 (tetrazine + trans cyclooctene conjugation (C11-OH bond)), or another ADC containing a different INX-SM payload, in which the INX-SM payload is conjugated to the antibody via tetrazine + trans cyclooctene conjugation and linked to the C11-OH; (vi) Ab-Gly-Glu-PAB-DMEDA-INX-3 or Ab-GlcA-PAB-DMEDA-INX-SM-3 (alkoxyamine + ketone conjugation (C11-OH linkage)), or another ADC containing a different INX-SM payload, in which the INX-SM payload is conjugated to the antibody via an alkoxyamine + ketone conjugation and linked to the C11-OH; (vii) Ab-Gly-Glu-PAB-DMEDA-INX-3 or Ab-GlcA-PAB-DMEDA-INX-SM-3 (azide + dibenzocyclooctyne conjugation (C17 linkage)), or another ADC containing a different INX-SM payload, wherein the INX-SM payload is conjugated to the antibody via an azide + dibenzocyclooctyne conjugation and C17 linked; (viii) Ab-Gly-Glu-PAB-DMEDA-INX-3 or Ab-GlcA-PAB-DMEDA-INX-SM-3 (haloacetyl + cysteine ​​conjugation (C17 linkage)), or another ADC containing a different INX-SM payload, wherein the INX-SM payload is conjugated to the antibody via azide + dibenzocyclooctyne conjugation and C17 linked; (ix) Ab-Gly-Glu-PAB-DMEDA-INX-3 or Ab-GlcA-PAB-DMEDA-INX-SM-3 (tetrazine + trans cyclooctene conjugation (C17 linkage)), or another ADC containing a different INX-SM payload, in which the INX-SM linker payload is conjugated to the antibody via a tetrazine + trans cyclooctene conjugation and C17 linked; (x) Ab-Gly-Glu-PAB-DMEDA-INX-3 or Ab-GlcA-PAB-DMEDA-INX-SM-3 (amine + glutamine conjugation using transglutaminase (C17 linkage)), or another ADC containing a different INX-SM payload, in which the INX-SM linker payload is conjugated to the antibody via amine + glutamine conjugation using transglutaminase and C17 linked; (xi) INX-SM-3-PAB-GlcA-Ab or INX-SM-3-PAB-Glu-Gly-Ab (alkoxyamine and ketone conjugation) (N-linked payload), or another ADC comprising a different INX-SM payload, in which the INX-SM linker payload is conjugated to the antibody via alkoxyamine and ketone conjugation and is N-linked; (xii) INX-SM-3-PAB-GlcA-Ab or INX-SM-3-PAB-Glu-Gly-Ab (haloacetyl conjugation) (N-linked payload), or another ADC comprising a different INX-SM payload in which the INX-SM linker payload is conjugated to the antibody via a haloacetyl conjugation and is N-linked; (xiii) INX-SM-3-PAB-GlcA-Ab or INX-SM-3-PAB-Glu-Gly-Ab (azide + dibenzocyclooctyne conjugation) (N-linked payload), or another ADC containing a different INX-SM payload, in which the INX-SM linker payload is conjugated to the antibody via an azide + dibenzocyclooctyne conjugation and is N-linked; (xiv) INX-SM-3-GlcA-Ab or INX-SM-3-Glu-Gly-Ab (N-hydroxysuccinimide conjugation) (N-linked payload), or another ADC comprising a different INX-SM payload, in which the INX-SM linker payload is conjugated to the antibody via N-hydroxysuccinimide conjugation and is N-linked; (xv) INX-SM-3-PAB-GlcA-Ab or INX-SM-3-PAB-Glu-Gly-Ab (azide + dibenzocyclooctyne conjugation) (N-linked payload), or another ADC containing a different INX-SM payload, in which the INX-SM linker payload is conjugated to the antibody via an azide + dibenzocyclooctyne conjugation and is N-linked; (xvi) INX-SM-3-PAB-GlcA-Ab or INX-SM-3-PAB-Glu-Gly-Ab (N-hydroxysuccinimide conjugation) (N-linked payload), or another ADC comprising a different INX-SM payload, in which the INX-SM linker payload is conjugated to the antibody via N-hydroxysuccinimide conjugation and is N-linked; (xvii) INX-SM-3-Glu-Gly-Ab or INX-SM-3-PAB-Glu-Gly-Ab (maleimide conjugation) (N-linked payload), or another ADC comprising a different INX-SM payload, wherein the INX-SM linker payload is conjugated to the antibody via maleimide conjugation and is N-linked; (xviii) INX-SM-3-Glu-Gly-Ab or INX-SM-3-PAB-Glu-Gly-Ab or INX-SM-3-PAB-GlcA-Ab (trans cyclooctene + tetrazine conjugation) (N-linked payload), or another ADC containing a different INX-SM payload, wherein the INX-SM linker payload is conjugated to the antibody via a trans cyclooctene + tetrazine conjugation and is N-linked; (xix) An antibody drug conjugate (ADC) selected from INX-SM-3-Glu-Gly-Ab or INX-SM-3-PAB-Glu-Gly-Ab or INX-SM-3-PAB-GlcA-Ab (amine conjugation) (N-linked payload), or another ADC containing a different INX-SM payload, in which the INX-SM linker payload is conjugated and N-linked to the antibody via a trans-cyclooctene + tetrazine conjugation.

[0031] An antibody drug conjugate (ADC) selected from: [ka] During the ceremony, Ab = antibody, preferably an antibody that binds to human immune cells, preferably an anti-VISTA antibody that binds to human VISTA immune cells at physiological pH; L=linker, AA = single, double, or triple amino acid sequence; NH Payload = [ka] REG is independently selected from the group consisting of hydrogen, alkyl, biphenyl, —CF3, —NO2, —CN, fluoro, bromo, chloro, alkoxyl, alkylamino, dialkylamino, alkyl-C(O)O—, alkylamino-C(O)—, and dialkylaminoC(O)—; [ka] Ab=antibody, L=linker, AA = single, double, or triple amino acid sequence; NH Payload = [ka] REG is independently selected from the group consisting of hydrogen, alkyl, biphenyl, —CF3, —NO2, —CN, fluoro, bromo, chloro, alkoxyl, alkylamino, dialkylamino, alkyl-C(O)O—, alkylamino-C(O)—, and dialkylaminoC(O)—; [ka] Ab=antibody, L=linker, AA = single, double, or triple amino acid sequence, or absent; NH Payload = [ka] REG is independently selected from the group consisting of hydrogen, alkyl, biphenyl, —CF3, —NO2, —CN, fluoro, bromo, chloro, alkoxyl, alkylamino, dialkylamino, alkyl-C(O)O—, alkylamino-C(O)—, and dialkylaminoC(O)—; RT=AA or [ka] [ka] Ab = antibody, optionally an anti-human VISTA antibody; L=linker, AA = single, double, or triple amino acid sequence; Payload = [ka] [ka] Ab = antibody, typically an antibody that binds to an antigen expressed on an immune cell, typically a human immune cell, e.g., VISTA; L=linker, AA = single, double, or triple amino acid sequence, or absent; Payload = [ka] RT=AA or [ka] It is another specific object of the present invention to provide an antibody drug conjugate (ADC) wherein

[0032] It is a specific object of the present invention to provide an antibody drug conjugate (ADC) as described above, wherein the linker comprises a cleavable or non-cleavable peptide or a sacrificial linker.

[0033] PAB and / or amino acids or peptides, optionally 1 to 12 amino acids, further optionally dipeptides, tripeptides, quattrapeptides, pentapeptides, further optionally Gly, Asn, Asp, Gln, Leu, Lys, Ala, Phe, Cit, Val, Val-Cit, Val-Ala, Val-Gly, Val-Gln, Ala-Val, Cit-Cit, Lys-Val-Cit, Asp-Val It is a specific object of the invention to provide an antibody drug conjugate (ADC) as described in any of the foregoing, which comprises a linker selected from -Ala, Ala-Ala-Asn, Asp-Val-Ala, Ala-Val-Cit, Ala-Asn-Val, βAla-Leu-Ala-Leu, Lys-Val-Ala, Val-Leu-Lys, Asp-Val-Cit, Val-Ala-Val, and Ala-Ala-Asn.

[0034] The following structure: [ka] wherein n=2-12, 2-10, 2-8, 2-6, 2-4, and A is an antibody or antigen-binding fragment thereof, preferably an antibody or antibody fragment that binds to an antigen expressed on an immune cell, preferably a human immune cell, and in an exemplary embodiment is an anti-human VISTA antibody.

[0035] Glucocorticoid agonist compounds of formula (I): [ka] During the ceremony, X is selected from phenyl, spiro[3.3]heptane, 3-6 membered heterocycle, cycloalkyl, spiroalkyl, spiroheterocycloalkyl, bicyclic alkyl, heterobicyclic alkyl, [1.1.1]bicyclopentane, bicyclo[2.2.2]octane, adamantane, and cubane, each of which can be independently substituted with 1-4 heteroatoms selected from F, Cl, Br, I, N, S, and O, and each of whose ring structures can include at least one skeletal heteroatom selected from N, S, and O, and optionally further substituted with 1-4 C1-3 alkyl or C1-3 perfluoroalkyl; Z is selected from phenyl, spiro[3.3]heptane, 3-6 membered heterocycle, cycloalkyl, spiroalkyl, spiroheterocycloalkyl, bicyclic alkyl, heterobicyclic alkyl, [1.1.1]bicyclopentane, bicyclo[2.2.2]octane, adamantane, and cubane, each of which can be independently substituted with 1-4 heteroatoms selected from F, Cl, Br, I, N, S, and O, and each of whose ring structures can include at least one skeletal heteroatom selected from N, S, and O, and optionally further substituted with 1-4 C1-3 alkyl or C1-3 perfluoroalkyl; Y is selected from CHR, O, S, and NR; E is selected from CH and O; G is selected from CH and N; Furthermore, when G is CH and X is phenyl, Z is not phenyl, the bond of G to X may optionally be selected from C alkyl and ethylene oxide, each of which may be independently substituted with 1-4 heteroatoms selected from N, S, and O, and optionally further substituted with 1-4 C alkyl; the bond of X to Z may occupy any available position on X and Z; The substituent NR1R2 may occupy any available position on Z; R1 is selected from H, linear or branched alkyl of 1 to 8 carbons, aryl, and heteroaryl groups, and the aryl and heteroaryl groups can be substituted with functional groups selected from alkyl, haloalkyl, halogen, biphenyl, nitro, nitrile, -OH, -O-alkyl, -NH2, alkylamino, dialkylamino, thiol, thioalkyl, guanidine, urea, carboxylic acid, alkoxyl, carboxamide, carboxylic acid ester, alkyl-C(O)O-, alkylamino-C(O)-, and dialkylaminoC(O)-; When R1 is H, R2 can be selected from H, linear or branched alkyl of 1 to 8 carbons, aryl, and heteroaryl groups, and the aryl and heteroaryl groups can be substituted with functional groups selected from alkyl, haloalkyl, halogen, biphenyl, nitro, nitrile, -OH, -O-alkyl, -NH2, alkylamino, dialkylamino, thiol, thioalkyl, guanidine, urea, carboxylic acid, alkoxyl, carboxamide, carboxylic acid ester, alkyl-C(O)O-, alkylamino-C(O)-, and dialkylaminoC(O)-; When R1 is H, a linear or branched alkyl of 1 to 8 carbons, or a heteroaryl, R2 is [(C=O)CH(W)NH]m-[C=O]-[V]kJ, C=O)OCH2-p-aminophenyl-NVJ, (C=O)OCH2-p-aminophenyl-N-[(C=O)CH(W)NH]m-[C=O]-[V]kJ, and [V]-(C=O)OCH-p-aminophenyl-N—[(C=O)CH(W)NH]-[C=O]-J; wherein m=1 to 6, k=0 to 1, and each occurrence of W may be independently selected from H, [(CH)R] where n=1 to 4, a branched alkyl chain terminating in R, and a linear or branched polyethylene oxide group containing 1 to 13 units; R3 is selected from H, methyl, ethyl, isopropyl, OH, O-alkyl, NH, NH-alkyl, N-dialkyl, SH, S-alkyl, guanidine, urea, carboxylic acid, carboxamide, carboxylic acid ester, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, wherein the aryl and heteroaryl substituents may be selected from alkyl, haloalkyl, halogen, biphenyl, nitro, nitrile, —OH, —O-alkyl, —NH, alkylamino, dialkylamino, thiol, thioalkyl, guanidine, urea, carboxylic acid, alkoxyl, carboxamide, carboxylic acid ester, alkyl-C(O)O—, alkylamino-C(O)—, and dialkylaminoC(O)—; V is an alkyl chain of 1 to 8 carbons, a linear or branched polyethylene oxide group containing 1 to 13 units, a linear or branched alkyl group containing 1 to 8 carbons, -O-alkyl, carboxylic acid, carboxamide, carboxylic acid ester, alkyl-C(O)O-, alkylamino-C(O)-, dialkylamino-C(O)-, a sequence of 1 to 3 amino acids, each amino acid independently selected from Glu, Gly, Asn, Asp, Gln, Leu, Lys, Ala, βAla, Phe, Val, and Cit. and a heteroaryl group, wherein the aryl and heteroaryl groups may be substituted with a functional group selected from alkyl, haloalkyl, halogen, biphenyl, nitro, nitrile, -OH, -NH2, alkylamino, dialkylamino, thiol, thioalkyl, guanidine, urea, carboxylic acid, alkoxyl, carboxamide, carboxylic acid ester, alkyl-C(O)O-, alkylamino-C(O)-, and dialkylaminoC(O)-; J is -NH2, N3, thio, cyclooctyne, -OH, -CO2H, transcyclooctene, alkynyl, propargyl, [ka] is a reactive group selected from wherein R32 is selected from Cl, Br, F, mesylate, and tosylate; R33 is selected from Cl, Br, I, F, OH, —ON-succinimidyl, —O-(4-nitrophenyl), —O-pentafluorophenyl, or —O-tetrafluorophenyl; and R34 is H, Me, tetrazine-H, and tetrazine-Me; R5 is -CH2OH, -CH2SH, -CH2Cl, -SCH2Cl, -SCH2F, -SCH2CF3, hydroxy, -OCH2CN, -OCH2Cl, -OCH2F, -OCH3, -OCH2CH3, -SCH2CN, and [ka] is selected from the group consisting of R6 and R7 are independently selected from hydrogen and C1-10 alkyl; Q is H, [ka] R8 can be C(O)R8, where R8 is a straight or branched alkyl of 1 to 8 carbons, or (C=O)NR4CHnNR4(C=O)OCH2-(V)nJ, where n=1-4 and R4=H, alkyl or branched alkyl, or P(O)OR4; A1 and A2 are independently selected from H and F; It is a specific object of this invention to provide glucocorticoid agonist compounds, in which all possible stereoisomers are claimed, unless otherwise specified.

[0036] Z, [ka] each of which may be independently substituted with 1 to 4 heteroatoms selected from F, Cl, Br, I, N, S, and O, and optionally further substituted with 1 to 4 C alkyl or C perfluoroalkyl groups; each of the ring structures may contain at least one additional skeletal heteroatom selected from N, S, and O; During the ceremony, each [ka] It is a specific object of the present invention to provide a glucocorticoid agonist compound as defined in any of the foregoing, wherein denotes a point of attachment to the remainder of the formula, each of which may be covalently bonded to the remainder of the formula via an additional heteroatom selected from N, S, and O.

[0037] Z-NR1, [ka] is selected from each of which may be independently substituted with 1 to 4 heteroatoms selected from F, Cl, Br, I, N, S, and O, and optionally further substituted with 1 to 4 C alkyl or C perfluoroalkyl groups; each of the ring structures may contain at least one additional skeletal heteroatom selected from N, S, and O; During the ceremony, each [ka] It is a specific object of the present invention to provide a glucocorticoid agonist compound as defined in any of the foregoing, wherein denotes a point of attachment to the remainder of the formula, each of which may be covalently bonded to the remainder of the formula via an additional heteroatom selected from N, S, and O.

[0038] Glucocorticoid agonist compounds having the structure of formula (II): [ka] During the ceremony, Y is selected from CH and O; E is selected from CH and O; G is selected from CH and N; L is selected from H and F; R5 is -CH2OH, -SCH2F, and [ka] is selected from A1 and A2 are independently selected from H and F; V is an alkyl chain of 1 to 8 carbons, a linear or branched polyethylene oxide group containing 1 to 13 units, a linear or branched alkyl group containing 1 to 8 carbons, -O-alkyl, carboxylic acid, carboxamide, carboxylic acid ester, alkyl-C(O)O-, alkylamino-C(O)-, dialkylamino-C(O)-, a sequence of 1 to 3 amino acids, each amino acid independently selected from Glu, Gly, Asn, Asp, Gln, Leu, Lys, Ala, βAla, Phe, Val, and Cit. and a heteroaryl group, wherein the aryl and heteroaryl groups may be substituted with a functional group selected from alkyl, haloalkyl, halogen, biphenyl, nitro, nitrile, -OH, -NH2, alkylamino, dialkylamino, thiol, thioalkyl, guanidine, urea, carboxylic acid, alkoxyl, carboxamide, carboxylic acid ester, alkyl-C(O)O-, alkylamino-C(O)-, and dialkylaminoC(O)-; J is -NH2, N3, thio, cyclooctyne, -OH, -CO2H, transcyclooctene, alkynyl, propargyl, [ka] is a reactive group selected from It is a specific object of the present invention to provide glucocorticoid agonist compounds wherein R32 is selected from Cl, Br, F, mesylate, and tosylate; R33 is selected from Cl, Br, I, F, OH, -ON-succinimidyl, -O-(4-nitrophenyl), -O-pentafluorophenyl, or -O-tetrafluorophenyl; and R34 is H, Me, tetrazine-H, and tetrazine-Me.

[0039] Possessing the structure of formula (III): [ka] During the ceremony, Y is selected from CH and O; E is selected from CH and O; G is selected from CH and N; L is selected from H and F; R5 is -CH2OH, -SCH2F, and [ka] is selected from A1 and A2 are independently selected from H and F; V is an alkyl chain of 1 to 8 carbons, a linear or branched polyethylene oxide group containing 1 to 13 units, a linear or branched alkyl group containing 1 to 8 carbons, -O-alkyl, carboxylic acid, carboxamide, carboxylic acid ester, alkyl-C(O)O-, alkylamino-C(O)-, dialkylamino-C(O)-, a sequence of 1 to 3 amino acids, each amino acid independently selected from Glu, Gly, Asn, Asp, Gln, Leu, Lys, Ala, βAla, Phe, Val, and Cit. and a heteroaryl group, wherein the aryl and heteroaryl groups may be substituted with a functional group selected from alkyl, haloalkyl, halogen, biphenyl, nitro, nitrile, -OH, -NH2, alkylamino, dialkylamino, thiol, thioalkyl, guanidine, urea, carboxylic acid, alkoxyl, carboxamide, carboxylic acid ester, alkyl-C(O)O-, alkylamino-C(O)-, and dialkylaminoC(O)-; J is -NH2, N3, thio, cyclooctyne, -OH, -CO2H, transcyclooctene, alkynyl, propargyl, [ka] is a reactive group selected from It is a specific object of the present invention to provide a glucocorticoid agonist compound as described in any of the foregoing, wherein R32 is selected from Cl, Br, F, mesylate, and tosylate; R33 is selected from Cl, Br, I, F, OH, -ON-succinimidyl, -O-(4-nitrophenyl), -O-pentafluorophenyl, or -O-tetrafluorophenyl; and R34 is H, Me, tetrazine-H, and tetrazine-Me. Any of the glucocorticoid agonist compounds described above, [ka] [ka] [ka] [ka] [ka] [ka] [ka] [ka] It is a specific object of the present invention to provide a glucocorticoid agonist compound selected from:

[0040] It is a specific object of the present invention to provide glucocorticoid agonist compounds as described above, i.e., of formula I, II, or III, wherein X or Z can be spiro[3.3]heptane or [1.1.1]bicyclopentane, and Y can be CH or O.

[0041] It is a specific object of the present invention to provide an antibody drug conjugate (ADC) comprising an antibody or antibody-binding fragment thereof, preferably one that binds to an antigen expressed by an immune cell, preferably a human immune cell, wherein the antibody or antibody-binding fragment is attached to at least one glucocorticoid agonist according to any one of the previous embodiments.

[0042] an ADC, [ka] [ka] [ka] [ka] [ka] [ka] [ka] [ka] [ka] [ka] [ka] It is a specific object of the present invention to provide an ADC selected from the group consisting of:

[0043] It is a specific object of the present invention to provide a composition comprising at least one glucocorticoid agonist compound, or steroid linker conjugate of Formula I, II, or III, as described above, or an ADC containing same, and a pharmaceutically acceptable carrier.

[0044] It is a specific object of the present invention to provide compositions as described above that are suitable for in vivo administration to a subject in need thereof.

[0045] It is a specific object of the present invention to provide a composition as described above that includes at least one additive.

[0046] It is a specific object of the present invention to provide a composition as described above which includes at least one stabilizer or buffering agent.

[0047] It is a specific object of the present invention to provide compositions as described above that are suitable for parenteral administration, optionally by injection.

[0048] It is a specific object of the present invention to provide a composition as described above that is suitable for injection into a subject in need thereof, optionally via intravenous, subcutaneous, intramuscular, intratumoral, or intrathecal injection.

[0049] It is a specific object of the present invention to provide compositions as described above that can be administered subcutaneously, intramuscularly, or intravenously.

[0050] It is a specific object of the present invention to provide a composition as described above contained in a device providing subcutaneous administration selected from the group consisting of a syringe, an injection device, an infusion pump, an injector pen, a needle-free device, an auto-injector, and a subcutaneous patch delivery system, optionally a device that delivers a fixed dose of a glucocorticoid receptor agonist or an ADC containing the same to a patient.

[0051] It is a specific object of the present invention to provide the use of any of the glucocorticoid agonist compounds or steroid-linker conjugates or ADCs described above, or compositions containing same, for treating, preventing, or inhibiting inflammation, allergy, or autoimmunity in a subject in need thereof.

[0052] It is a specific object of the present invention to provide a glucocorticoid agonist compound, or a steroid linker conjugate of Formula I, II, or III, as described above, or an ADC containing, or a composition containing, for use in the preparation of a medicament for treating, preventing, or inhibiting an inflammatory or autoimmune or allergic response in a subject in need thereof.

[0053] It is a specific object of the present invention to provide a method of treatment and / or prevention comprising administering to a subject in need thereof at least one glucocorticoid agonist compound as described above, or a steroid linker conjugate of Formula I, II, or III, or an ADC containing, or a composition containing, as described above.

[0054] It is a specific object of the invention to provide a use, medicament, composition or method as described in any of the foregoing for the treatment of allergy, autoimmunity, transplantation, gene therapy, inflammation, GVHD or sepsis in a human subject, or for treating or preventing inflammatory, autoimmune or allergic side effects associated with any of the foregoing conditions.

[0055] It is a specific object of the present invention to provide a use, medicament, composition or method according to any of the foregoing, which is for acute use.

[0056] It is a specific object of the present invention to provide a use, medicament, composition or method according to any of the foregoing, which is for chronic use.

[0057] It is a specific object of the present invention to provide a use, medicament, composition or method according to any of the foregoing, which is for maintenance therapy.

[0058] For the treatment or prevention of acute or chronic inflammation and associated autoimmune and inflammatory indications, the condition optionally being, among others, acquired aplastic anemia+, acquired hemophilia+, acute disseminated encephalomyelitis (ADEM)+, acute hemorrhagic leukoencephalitis (AHLE) / Hurst disease+, primary agammaglobulinemia+, alopecia areata+, ankylosing spondylitis (AS), anti-NMDA receptor encephalitis+, antiphospholipid syndrome (APS)+, arteriosclerosis, autism spectrum disorder (ASD), autoimmune Addison's disease (AAD)+, autoimmune autonomic neuropathy / autoimmune autonomic ganglia. Disorders (AAG), autoimmune encephalitis+, autoimmune gastritis, autoimmune hemolytic anemia (AIHA)+, autoimmune hepatitis (AIH)+, autoimmune hyperlipidemia, autoimmune hypophysitis / lymphocytic hypophysitis+, autoimmune inner ear disease (AIED)+, autoimmune lymphoproliferative syndrome (ALPS)+, autoimmune myocarditis, autoimmune oophoritis+, autoimmune orchitis+, autoimmune pancreatitis (AIP) / immunoglobulin G4-related disease (IgG4-RD)+, autoimmune polyglandular syndrome type I, II, and III+, autoimmune progesterone-induced dermatitis+, autoimmune sudden hearing loss (SNHL), Achalasia, Addison's disease, Adult Still's disease, Agammaglobulinemia, Alopecia areata, Amyloidosis, Ankylosing spondylitis, Anti-GBM / Anti-TBM Nephritis, Antiphospholipid Syndrome, Autoimmune Angioedema, Autoimmune Autonomic Neuropathy, Autoimmune Encephalomyelitis, Autoimmune Hepatitis, Autoimmune Inner Ear Disease (AIED), Autoimmune Myocarditis, Autoimmune Oophoritis, Autoimmune Orchitis, Autoimmune Pancreatitis, Autoimmune Retinopathy, Autoimmune Urticaria, Axonal and Neuronal Neuropathy (AMAN), Baro's disease, Behçet's disease, Benign Mucous Membrane Pemphigoid, Bullous Pemphigoid, Castleman's Disease (CD), Celia Chronic inflammatory demyelinating polyneuropathy (CIDP), chronic relapsing multiple myelitis (CRMO), Churg-Strauss syndrome (CSS) or eosinophilic granulomatosis (EGPA), cicatricial pemphigoid, Cogan's syndrome, cold agglutinin disease, congenital heart block, Coxsackie myocarditis, CREST syndrome, type 1 diabetes, dermatitis herpetiformis, dermatomyositis, Devic's disease (neuromyelitis optica), discoid lupus, Dressler's syndrome, endometriosis, eosinophilic esophagitis (EoE), eosinophilic fasciitis, erythema nodosum, essential mixed cryoglobulinemia, Evans' syndrome, fibromyalgia,Fibrotic alveolitis, fibrosing alveolitis, giant cell myocarditis, glomerulonephritis, Goodpasture's syndrome, granulomatosis with polyangiitis, Graves' disease, Guillain-Barré syndrome, Hashimoto's thyroiditis, hemolytic anemia, Henoch-Schönlein purpura (HSP), herpes gestationis or pemphigoid of gestationis (PG), hidradenitis suppurativa (HS) (acne inversa), hypogammaglobulinemia, IgA nephropathy, IgG4-related sclerosing disease, immune thrombocytopenic purpura (ITP), inclusion body myositis (IBM), interstitial cystitis (IC), juvenile arthritis, juvenile diabetes mellitus (type 1 diabetes), juvenile myositis (JM), Kawasaki disease, Ran Bart-Eaton syndrome, leukocytoclastic vasculitis, lichen planus, lichen sclerosus, lignified conjunctivitis, linear immunoglobulin A disease (LAD), lupus (including nephritic and cutaneous), chronic Lyme disease, Meniere's disease, microscopic polyangiitis (MPA), mixed connective tissue disease (MCTD), Mooren's ulcer, Mukka-Habermann disease, multiple motor neuropathy (MMN) or MMNCB, multiple sclerosis, myasthenia gravis, myelin oligodendrocyte glycoprotein antibody disorder, myositis, narcolepsy, neonatal lupus, neuromyelitis optica, neutropenia, ocular cicatricial pemphigoid, optic neuritis, opsoclonus Oss-Myoclonus Syndrome (OMS), Relapsing Rheumatoid Arthritis (PR), PANDAS, Paraneoplastic Cerebellar Degeneration (PCD), Paroxysmal Nocturnal Hemoglobinuria (PNH), Parry-Romberg Syndrome, Parsplanitis (Peripheral Uveitis), Parsonage-Turner Syndrome, Pemphigus, Peripheral Neuropathy, Perivenous Encephalomyelitis, Pernicious Anemia (PA), POEMS Syndrome, Polyarteritis Nodosa, Polyglandular Syndrome Types I, II, III, Polymyalgia Rheumatica, Polymyositis, Post-Myocardial Infarction Syndrome, Post-Pericardiotomy Syndrome, Primary Biliary Cholangitis, Primary Sclerosing Cholangitis, Progesterone-Induced Dermatitis, Psoriasis Arthritis, Pure Red Cell Aplasia (PRCA), Pyoderma Gangrenosum, Raynaud's Phenomenon, Reactive Arthritis, Reflex Sympathetic Dystrophy, Relapsing Polychondritis, Restless Legs Syndrome (RLS), Retroperitoneal Fibrosis, Rheumatic Fever, Rheumatoid Arthritis, Sarcoidosis, Schmidt's Syndrome, Scleritis, Scleroderma, Sjogren's Syndrome, Sperm and Testicular Autoimmunity, Stiff Person Syndrome (SPS), Subacute Bacterial Endocarditis (SBE), Susac's Syndrome, Sympathetic Ophthalmia (SO), Takayasu's Arteritis, Temporal Arteritis / Giant Cell Arteritis, Thrombocytopenic Purpura (TTP), Thyroid Eye Disease (TED),It is a specific object of the present invention to provide a use, medicament, composition, or method as described in any of the foregoing, including for the treatment of Tolosa-Hunt syndrome (THS), transverse myelitis, type 1 diabetes, undifferentiated connective tissue disease (UCTD), uveitis, vasculitis, vitiligo, and Vogt-Koyanagi-Harada disease.

[0059] It is a specific object of the present invention to provide a use, medicament, composition or method as defined in any of the foregoing for the treatment or prevention of acute or chronic inflammation and its associated autoimmune and inflammatory and allergic indications or side effects, wherein the condition optionally includes severe asthma, giant cell arteritis, ANKA vasculitis, and IBD (colitis and Crohn's disease).

[0060] It is a specific object of the invention to provide a use, medicament, composition or method as described in any of the foregoing for the treatment or prevention of a condition selected from rheumatoid arthritis, juvenile idiopathic arthritis, psoriatic arthritis, ankylosing spondylitis, adult Crohn's disease, pediatric Crohn's disease, ulcerative colitis, plaque psoriasis, hidradenitis suppurativa, uveitis, Behcet's disease, spondyloarthropathy or psoriasis.

[0061] One or more of the following: (i) chronic, acute, or temporary allergic, inflammatory, or inflammatory conditions, e.g., chronic, acute, temporary, and / or remitting / relapsing; (ii) conditions that are only primarily treatable effectively with high doses of steroids, optionally asthma, COPD, polymyalgia rheumatica and / or giant cell arteritis, where the patient is or has been treated with optionally high steroid doses; (iii) conditions with comorbidities that limit steroid use, optionally including diabetes, nonalcoholic steatohepatitis (NASH), morbid obesity, avascular necrosis / osteonecrosis (AVN), glaucoma, steroid-induced hypertension, severe skin fragility, and / or osteoarthritis; (iv) conditions where safe long-term treatments are available but where several months of induction with high dose steroids is desired, optionally where several months of induction with high dose steroids is therapeutically justified, such as AAV, polymyositis, dermatomyositis, lupus, inflammatory lung disease, autoimmune hepatitis, inflammatory bowel disease, immune thrombocytopenia, autoimmune hemolytic anemia, gout patients; (v) Skin conditions requiring short / long term treatment, optionally conditions of uncertain treatment or duration and / or conditions with no effective alternative to steroid administration, optionally other severe immune-mediated skin conditions such as Stevens-Johnson, other severe drug rash conditions, conditions with widespread contact dermatitis, PG, LCV, erythroderma, and the like; (vi) conditions treated with high-dose corticosteroids for exacerbations / recurrences, optionally COPD, asthma, lupus, gout, pseudogout; (vii) immune-mediated neurological disorders such as small fiber neuropathy, MS (subset), chronic inflammatory demyelinating polyneuropathy, myasthenia gravis, and the like; (viii) optionally, hematology / oncology indications where high doses of steroids are therapeutically justified or beneficial; (ix) ophthalmic conditions, optionally uveitis, iritis, scleritis, and the like; (x) conditions associated with permanent or very long-term adrenal insufficiency or secondary adrenal insufficiency, optionally, iatrogenic Addisonian crisis; (xi) conditions often treated with long-term low-dose steroids, optionally lupus, RA, psoriasis, vasculitis, or (xii) It is a specific object of the present invention to provide a use, medicament, composition or method as defined in any of the foregoing for the treatment or prevention in a patient having any combination of any of the foregoing.

[0062] It is a specific object of the present invention to provide a use, medicament, composition or method as described in any of the foregoing for the treatment or prevention in special classes of patients at risk of toxicity in steroid treatment, such as pregnant / lactating women, pediatric patients, optionally pediatric patients with growth disorders or cataracts, wherein the patient is further treated with another active agent.

[0063] It is a specific object of the invention to provide a use, medicament, composition or method according to any of the foregoing, wherein the patient is further treated with an immunomodulatory antibody or fusion protein selected from an immunoinhibitory antibody or fusion protein targeting one or more of CTLA4, PD-1, PDL-1, LAG-3, TIM-3, BTLA, B7-H4, B7-H3, VISTA, and / or an agonistic antibody or fusion protein targeting one or more of CD40, CD137, OX40, GITR, CD27, CD28 or ICOS.

[0064] It is a specific object of the present invention to provide a use, medicament, composition, or method according to any of the foregoing, wherein the ADC comprises an antibody or antigen-binding fragment (“A”) comprising an antigen-binding region that specifically binds to human V-domain Ig suppressor of T-cell activation (human VISTA), and wherein the ADC, upon administration to a subject in need thereof, is preferentially delivered to VISTA-expressing immune cells, optionally one or more of monocytes, myeloid cells, T cells, Tregs, NK cells, neutrophils, dendritic cells, eosinophils, macrophages, NK cells, and endothelial cells, resulting in functional internalization of the anti-inflammatory agent into one or more of said immune cells.

[0065] It is a specific object of the present invention to provide a use, agent, composition or method as described in any of the foregoing, wherein the ADC optionally comprises an anti-human VISTA antibody or antibody fragment that preferentially binds to VISTA-expressing cells at physiological pH (≈7.5) with a pK of at most 70 hours in human VISTA knock-in rodents.

[0066] It is a specific object of the invention to provide a use, medicament, composition or method as described in any of the foregoing, wherein the ADC comprises an anti-human VISTA antibody or antibody fragment having a pK in cynomolgus monkeys or humans at physiological pH of at most 3.5±0.5 days, more typically at most 48 hours, at most 36 hours, at most 24 hours, at most 18 hours or at most 12 hours.

[0067] It is a specific object of the invention to provide a use, medicament, composition or method as described in any of the foregoing, wherein the ADC comprises an anti-human VISTA antibody or antibody fragment having a pK in cynomolgus monkeys or humans at physiological pH of at most 2.8 or 2.3 or 1.5 days, or 1 day, or 12 hours or 8 hours ± 0.5 days.

[0068] It is a specific object of the invention to provide a use, medicament, composition or method according to any of the foregoing, wherein the ADC comprises an anti-human VISTA antibody or antibody fragment having a pK of at most 6-12 hours in human VISTA rodents at physiological pH.

[0069] It is a specific object of the present invention to provide a use, medicament, composition or method as described in any of the foregoing, wherein the ADC comprises an anti-human VISTA antibody or antibody fragment, which comprises a linker that is cleaved upon internalization of the ADC into one or more of VISTA-expressing immune cells, optionally T cells, CD4 or CD8 T cells, Tregs, NK cells, neutrophils, monocytes, myeloid cells, dendritic cells, macrophages, eosinophils, and endothelial cells, resulting in release of a therapeutically effective amount of the anti-inflammatory agent (glucocorticoid agonist) within the immune cell.

[0070] It is a specific object of the present invention to provide a use, medicament, composition or method according to any of the foregoing, wherein the ADC comprises an anti-human VISTA antibody or antibody fragment, and wherein the anti-VISTA antibody or antigen-binding fragment has an in vivo serum half-life in primates, optionally cynomolgus monkeys, of about 2.3 days at physiological pH (about pH 7.5).

[0071] It is a specific object of the present invention to provide any of the aforementioned uses, medicaments, compositions, or methods, wherein the ADC comprises an anti-human VISTA antibody or antibody fragment, and the anti-VISTA antibody or antigen-binding fragment has an in vivo serum half-life in serum at physiological pH (approximately pH 7.5) in human VISTA knock-in rodents of 70 hours or less, 60 hours or less, 50 hours or less, 40 hours or less, 30 hours or less, 24 hours or less, 22 to 24 hours or less, 20 to 22 hours or less, 18 to 20 hours or less, 16 to 18 hours or less, 14 to 16 hours or less, 12 to 14 hours or less, 10 to 12 hours or less, 8 to 10 hours or less, 6 to 8 hours or less, 4 to 6 hours or less, 2 to 4 hours or less, 1 to 2 hours or less, 0.5 to 1.0 hours or less, or 0.1 to 0.5 hours or less.

[0072] It is a specific object of the invention to provide a use, medicament, composition or method according to any of the foregoing, wherein the ADC comprises an anti-human VISTA antibody or antibody fragment and the PD / PK ratio of the ADC, when used in vivo, is at least 2:1, 3:1, 4:1, 5:1, 6:1, 7:1, 8:1, 9:1, 10:1, 11:1, 12:1, 13:1, 14:1 or more in a human VISTA knock-in rodent, or a human or non-human primate, optionally a cynomolgus monkey.

[0073] It is a specific object of the invention to provide a use, medicament, composition or method according to any of the foregoing, wherein the ADC comprises an anti-human VISTA antibody or antibody fragment, and wherein the PD of the ADC is at least 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, or 14 days, 2 to 4 weeks, 1 month, or longer in any one of a rodent, or a human or non-human primate, optionally a cynomolgus monkey.

[0074] It is a specific object of the invention to provide a use, medicament, composition or method according to any of the foregoing, wherein the ADC comprises an antibody or antibody fragment that specifically binds to a human immune cell expressed antigen, e.g., an anti-human VISTA antibody or antibody fragment, and the antibody comprises an Fc region with impaired or intact FcR binding.

[0075] It is a specific object of the invention to provide a use, medicament, composition or method according to any of the foregoing, wherein the ADC comprises an antibody or antibody fragment that targets a human immune cell expressed antigen, for example an anti-human VISTA antibody or antibody fragment comprising a human IgG1, IgG2, IgG3, or IgG4 Fc region with impaired or intact FcR binding.

[0076] It is a specific object of the invention to provide a use, medicament, composition or method according to any of the foregoing, wherein the ADC comprises an antibody or antibody fragment that specifically binds to a human immune cell expressed antigen, for example an anti-human VISTA antibody or antibody fragment comprising a human IgG1 Fc region with impaired FcR binding.

[0077] It is a specific object of the invention to provide a use, medicament, composition or method as described in any of the foregoing, wherein the ADC comprises an antibody or antibody fragment that specifically binds to a human immune cell expressed antigen, for example, an anti-human VISTA antibody or antibody fragment comprising a human or non-human primate constant or Fc region that has been modified to impair or eliminate binding to at least two native human Fc gamma receptors.

[0078] It is a specific object of the invention to provide a use, medicament, composition or method as described in any of the foregoing, wherein the ADC comprises an antibody or antibody fragment that specifically binds to a human immune cell expressed antigen, for example an anti-human VISTA antibody or antibody fragment comprising a human or non-human primate constant or Fc region that has been modified to impair or eliminate binding to any one, two, three, four or all five of the following FcRs: hFcγRI (CD64), FcyRIIA or hFcyRIIB, (CD32 or CD32A), and FcγRIIIA (CD16A) or FcγRIIIB (CD16B).

[0079] It is a specific object of the invention to provide a use, medicament, composition or method according to any of the foregoing, wherein the ADC comprises an antibody or antibody fragment that specifically binds to a human immune cell expressed antigen, for example an anti-human VISTA antibody or antibody fragment comprising a human IgG2 kappa backbone, optionally with V234A / G237A / P238S / H268A / V309L / A330S / P331S silencing mutations in the Fc region.

[0080] It is a specific object of the invention to provide a use, medicament, composition or method according to any of the foregoing, wherein the ADC comprises an antibody or antibody fragment that specifically binds to a human immune cell expressed antigen, for example an anti-human VISTA antibody or antibody fragment comprising an IgG1 / kappa backbone with L234A / L235A silencing mutations in the Fc region, optionally with mutations that impair complement (C1Q) binding.

[0081] It is a specific object of the invention to provide a use, medicament, composition or method according to any of the foregoing, wherein the ADC comprises an antibody or antibody fragment that specifically binds to a human immune cell expressed antigen, for example an anti-human VISTA antibody or antibody fragment comprising a human IgG1 / kappa backbone, optionally with L234A / L235A silencing mutations and E269R and E233A mutations in the Fc region.

[0082] It is a specific object of the present invention to provide a use, medicament, composition, or method according to any of the foregoing, wherein the ADC comprises an antibody or antibody fragment that specifically binds to a human immune cell-expressed antigen, e.g., an anti-human VISTA antibody or antibody fragment, and wherein binding of the antibody or antigen-binding fragment to an immune cell does not directly agonize or antagonize the immune cell-expressed antigen-mediated effect on immunity, e.g., a VISTA-mediated effect on immunity.

[0083] It is a specific object of the invention to provide a use, medicament, composition or method according to any of the foregoing, wherein the ADC comprises an antibody or antibody fragment that specifically binds to a human immune cell expressed antigen, for example an anti-human VISTA antibody or antibody fragment comprising a human IgG1, IgG2, IgG3, or IgG4 Fc region, and wherein endogenous FcR binding is intact.

[0084] It is a specific object of the invention to provide a use, medicament, composition or method as described in any of the foregoing, wherein the ADC comprises an antibody or antibody fragment that specifically binds to a human immune cell-expressed antigen, for example an anti-human VISTA antibody or antibody fragment comprising a native (unmodified) human IgG2 Fc region.

[0085] It is a specific object of the invention to provide a use, medicament, composition, or method as described in any of the foregoing, wherein the ADC comprises an antibody or antibody fragment that specifically binds to a human immune cell-expressed antigen, e.g., an anti-human VISTA antibody or antibody fragment, and wherein the antibody or antigen-binding fragment comprises a KD in the range of 0.0001 nM to 10.0 nM, 0.001 to 1.0 nM, or 0.01 to 0.7 or less, as determined by surface plasmon resonance (SPR) at 24°C or 37°C.

[0086] It is a specific object of the invention to provide a use, medicament, composition or method according to any of the foregoing, wherein the ADC comprises an antibody or antibody fragment that specifically binds to a human immune cell-expressed antigen, e.g., an anti-human VISTA antibody or antibody fragment, and wherein the antibody or antigen-binding fragment comprises a KD of 0.13 to 0.64 nM as determined by surface plasmon resonance (SPR) at 24°C or 37°C.

[0087] It is a specific object of the invention to provide a use, medicament, composition or method according to any of the foregoing, wherein the ADC optionally comprises an antibody or antibody fragment that specifically binds to a human immune cell expressed antigen, such as an anti-human VISTA antibody or antibody fragment, and the drug to antibody ratio is in the range of 1:1 to 12:1.

[0088] It is a specific object of the invention to provide a use, medicament, composition or method according to any of the foregoing, wherein the ADC optionally comprises an anti-human VISTA antibody or antibody fragment, and the drug to antibody ratio is in the range of 2-12:1, 2-8:1, 4-8:1, or 6-8:1.

[0089] It is a specific object of the invention to provide a use, medicament, composition or method according to any of the foregoing, wherein the ADC comprises an antibody or antibody fragment that specifically binds to a human immune cell expressed antigen, e.g., an anti-human VISTA antibody or antibody fragment, and the drug to antibody ratio is about 8:1 (n=8), or about 4:1 (n=4).

[0090] It is a specific object of the invention to provide a use, medicament, composition or method as described in any of the foregoing, wherein the ADC comprises an antibody or antibody fragment that specifically binds to a human immune cell expressed antigen, for example an anti-human VISTA antibody or antibody fragment that internalizes one or more of monocytes, myeloid cells, T cells, Tregs, macrophages, and neutrophils.

[0091] It is a specific object of the invention to provide a use, medicament, composition or method as described in any of the foregoing, wherein the ADC comprises an antibody or antibody fragment that specifically binds to a human immune cell expressed antigen, e.g., an anti-human VISTA antibody or antibody fragment that does not appreciably internalize B cells.

[0092] It is a specific object of the invention to provide a use, medicament, composition or method as described in any of the foregoing, wherein the ADC comprises an antibody or antibody fragment that specifically binds to a human immune cell expressed antigen, e.g., an anti-human VISTA antibody or antibody fragment, which, when administered to a subject in need thereof, enhances efficacy and / or reduces adverse side effects, such as toxicity, associated with the anti-inflammatory agent, compared to the same dose of the anti-inflammatory agent administered in naked (unconjugated) form.

[0093] It is a specific object of the invention to provide a use, medicament, composition or method according to any of the foregoing, wherein the ADC optionally comprises an antibody or antibody fragment that specifically binds to a human immune cell expressed antigen, such as an anti-human VISTA antibody or antibody fragment, and wherein a glucocorticoid is optionally conjugated to the antibody or antigen-binding fragment via an interchain disulfide.

[0094] It is a specific object of the invention to provide a use, medicament, composition or method according to any of the foregoing, wherein the ADC comprises an antibody or antibody fragment that specifically binds to a human immune cell expressed antigen, for example an anti-human VISTA antibody or antibody fragment comprising an esterase-sensitive linker.

[0095] It is a specific object of the invention to provide a use, medicament, composition or method according to any of the foregoing, wherein the ADC comprises an antibody or antibody fragment that specifically binds to a human immune cell expressed antigen, such as an anti-human VISTA antibody or antibody fragment, and the cleavable linker is susceptible to one or more of acid-induced cleavage, photo-induced cleavage, peptidase-induced cleavage, esterase-induced cleavage, and disulfide bond cleavage.

[0096] It is a specific object of the present invention to provide a use, medicament, composition or method as described in any of the foregoing, wherein the ADC comprises an antibody or antibody fragment that specifically binds to a human immune cell-expressed antigen, such as an anti-human VISTA antibody or antibody fragment, and the anti-VISTA antigen-binding fragment comprised in the ADC comprises a Fab, F(ab')2, or scFv antibody fragment.

[0097] The ADC comprises an anti-human VISTA antibody or antibody fragment, wherein the anti-VISTA antibody or antibody fragment comprises the same CDRs as an antibody having the sequence of Figure 8, 10, or 12, or optionally (i) V of SEQ ID NOs: 100, 101, and 102 H CDRs and V of SEQ ID NOs: 103, 104, and 105 L those containing CDRs, (ii) V of SEQ ID NOs: 110, 111, and 112 H CDRs and V of SEQ ID NOs: 113, 114, and 115 L those containing CDRs, (iii) V of SEQ ID NOs: 120, 121, and 122 H CDRs and V of SEQ ID NOs: 123, 124, and 125 L those containing CDRs, (iv) V of SEQ ID NOs: 130, 131, and 132 H CDRs and V of SEQ ID NOs: 133, 134, and 135 L those containing CDRs, (v) V of SEQ ID NOs: 140, 141, and 142 H CDRs and V of SEQ ID NOs: 143, 144, and 145 L those containing CDRs, (vi) V of SEQ ID NOs: 150, 151, and 152 H CDRs and V of SEQ ID NOs: 153, 154, and 155 L those containing CDRs, (vii) V of SEQ ID NOs: 160, 161, and 162 H CDRs and V of SEQ ID NOs: 163, 164, and 165 L those containing CDRs, (viii) V of SEQ ID NOs: 170, 171, and 172 H CDRs and V of SEQ ID NOs: 173, 174, and 175 L those containing CDRs, (ix) V of SEQ ID NOs: 180, 181, and 182 H CDRs and V of SEQ ID NOs: 183, 184, and 185 L those containing CDRs, (x) V of SEQ ID NOs: 190, 191, and 192 H CDRs and V of SEQ ID NOs: 193, 194, and 195 L those containing CDRs, (xi) V of SEQ ID NOs: 200, 201, and 202 H CDRs and V of SEQ ID NOs: 203, 204, and 205 L those containing CDRs, (xii) V of SEQ ID NOs: 210, 211, and 212 H CDRs and V of SEQ ID NOs: 213, 214, and 215 L those containing CDRs, (xiii) V of SEQ ID NOs: 220, 221, and 222 H CDRs and V of SEQ ID NOs: 223, 224, and 225 L those containing CDRs, (xiv) V of SEQ ID NOs: 230, 231, and 232 H CDRs and V of SEQ ID NOs: 233, 234, and 235 L those containing CDRs, (xv) V of SEQ ID NOs: 240, 241, and 242 H CDRs and V of SEQ ID NOs: 243, 244, and 245 L those containing CDRs, (xvi) V of SEQ ID NOs: 250, 251, and 252 H CDRs and V of SEQ ID NOs: 253, 254, and 255 L those containing CDRs, (xvii) VH CDRs of SEQ ID NOs: 260, 261, and 262, and VH CDRs of SEQ ID NOs: 263, 264, and 265 L those containing CDRs, (xviii) V of SEQ ID NOs: 270, 271, and 272 H CDRs and V of SEQ ID NOs: 273, 274, and 275 L those containing CDRs, (xix) V of SEQ ID NOs: 280, 281, and 282 H CDRs and V of SEQ ID NOs: 283, 284, and 285 L those containing CDRs, (xx) V of SEQ ID NOs: 290, 291, and 292 H CDRs and V of SEQ ID NOs: 293, 294, and 295 L those containing CDRs, (xxi) V of SEQ ID NOs: 300, 301, and 302 H CDRs and V of SEQ ID NOs: 303, 304, and 305 L those containing CDRs, (xxii) V of SEQ ID NOs: 310, 311, and 312 H CDRs and V of SEQ ID NOs: 313, 314, and 315 L those containing CDRs, (xxiii) V of SEQ ID NOs: 320, 321, and 322 H CDRs and V of SEQ ID NOs: 323, 324, and 325 L those containing CDRs, (xxiv) V of SEQ ID NOs: 330, 331, and 332 H CDRs and V of SEQ ID NOs: 333, 334, and 335 L those containing CDRs, (xxv) V of SEQ ID NOs: 340, 341, and 342 H CDRs and V of SEQ ID NOs: 343, 344, and 345 L those containing CDRs, (xxvi) V of SEQ ID NOs: 350, 351, and 352 H CDRs and V of SEQ ID NOs: 353, 354, and 355 L those containing CDRs, (xxvii) V of SEQ ID NOs: 360, 361, and 362 H CDRs and V of SEQ ID NOs: 363, 364, and 365 L those containing CDRs, (xxviii) V of SEQ ID NOs: 370, 371, and 372 H CDRs and V of SEQ ID NOs: 373, 374, and 375 L those containing CDRs, (xxix) V of SEQ ID NOs: 380, 381, and 382 H CDRs and V of SEQ ID NOs: 383, 384, and 385 L those containing CDRs, (xxx) V of SEQ ID NOs: 390, 391, and 392 H CDRs and V of SEQ ID NOs: 393, 394, and 395 L those containing CDRs, (xxxi) V of SEQ ID NOs: 400, 401, and 402 H CDRs and V of SEQ ID NOs: 403, 404, and 405 L those containing CDRs, (xxxii) V of SEQ ID NOs: 410, 411, and 412 H CDRs and V of SEQ ID NOs: 413, 414, and 415 L those containing CDRs, (xxxiii) V of SEQ ID NOs: 420, 421, and 422 H CDRs and V of SEQ ID NOs: 423, 424, and 425 L those containing CDRs, (xxxiv) V of SEQ ID NOs: 430, 431, and 432 H CDRs and V of SEQ ID NOs: 433, 434, and 435 L those containing CDRs, (xxxv) V of SEQ ID NOs: 440, 441, and 442 H CDRs and V of SEQ ID NOs: 443, 444, and 445 L those containing CDRs, (xxxvi) V of SEQ ID NOs: 450, 451, and 452 H CDRs and V of SEQ ID NOs: 453, 454, and 455 L those containing CDRs, (xxxvii) V of SEQ ID NOs: 460, 461, and 462 H CDRs and V of SEQ ID NOs: 463, 464, and 465 L those containing CDRs, (xxxviii) V of SEQ ID NOs: 470, 471, and 472 H CDRs and V of SEQ ID NOs: 473, 474, and 475 L those containing CDRs, (xxxix) V of SEQ ID NOs: 480, 481, and 482 H CDRs and V of SEQ ID NOs: 483, 484, and 485 L those containing CDRs, (xl) V of SEQ ID NOs: 490, 491, and 492 H CDRs and VL CDR polypeptides of SEQ ID NOs: 493, 494, and 495; (xli) V of SEQ ID NOs: 500, 501, and 502 H CDRs and VL CDR polypeptides of SEQ ID NOs: 503, 504, and 505; (xlii) V of SEQ ID NOs: 510, 511, and 512 H CDRs and VL CDR polypeptides of SEQ ID NOs: 513, 514, and 515; (xliii) V of SEQ ID NOs: 520, 521, and 522 H CDRs and VL CDR polypeptides of SEQ ID NOs: 523, 524, and 525; (xliv) V of SEQ ID NOs: 530, 531, and 532 H CDRs and VL CDR polypeptides of SEQ ID NOs: 533, 534, and 535; (xlv) V of SEQ ID NOs: 540, 541, and 542 H CDRs and VL CDR polypeptides of SEQ ID NOs: 543, 544, and 545; (xlvi) V of SEQ ID NOs: 550, 551, and 552 H CDRs and VL CDR polypeptides of SEQ ID NOs: 553, 554, and 555; (xlvii) V of SEQ ID NOs: 560, 561, and 562 H CDRs and V of SEQ ID NOs: 563, 564, and 565 L those containing CDRs, (xlviii) V of SEQ ID NOs: 570, 571, and 572 H CDRs and V of SEQ ID NOs: 573, 574, and 575 L those containing CDRs, (xlix) V of SEQ ID NOs: 580, 581, and 582 H CDRs and V of SEQ ID NOs: 583, 584, and 585 L those containing CDRs, (l) V of SEQ ID NOs: 590, 591, and 592 H CDRs and V of SEQ ID NOs: 593, 594, and 595 L containing CDRs, (li) V of SEQ ID NOs: 600, 601, and 602 H CDRs and V of SEQ ID NOs: 603, 604, and 605 L those containing CDRs, (lii) V of SEQ ID NOs: 610, 611, and 612 H CDRs and V of SEQ ID NOs: 613, 614, and 615 L those containing CDRs, (liii) V of SEQ ID NOs: 620, 621, and 622 H CDRs and V of SEQ ID NOs: 623, 624, and 625 L those containing CDRs, (liv) V of SEQ ID NOs: 630, 631, and 632 H CDRs and V of SEQ ID NOs: 633, 634, and 635 L those containing CDRs, (lv) V of SEQ ID NOs: 640, 641, and 642 H CDRs and V of SEQ ID NOs: 643, 644, and 645 L those containing CDRs, (lvi) V of SEQ ID NOs: 650, 651, and 652 H CDRs and V of SEQ ID NOs: 653, 654, and 655 L those containing CDRs, (lvii) V of SEQ ID NOs: 660, 661, and 662 H CDRs and V of SEQ ID NOs: 663, 664, and 665 L those containing CDRs, (lviii) V of SEQ ID NOs: 670, 671, and 672 H CDRs and V of SEQ ID NOs: 673, 674, and 675 L those containing CDRs, (lix) V of SEQ ID NOs: 680, 681, and 682 H CDRs and V of SEQ ID NOs: 683, 684, and 685 L those containing CDRs, (lx) V of SEQ ID NOs: 690, 691, and 692 H CDRs and V of SEQ ID NOs: 693, 694, and 695 L those containing CDRs, (lxi) V of SEQ ID NOs: 700, 701, and 702 H CDRs and V of SEQ ID NOs: 703, 704, and 705 L those containing CDRs, (lxii) V of SEQ ID NOs: 710, 711, and 712 H CDRs and V of SEQ ID NOs: 713, 714, and 715 L those containing CDRs, (lxiii) V of SEQ ID NOs: 720, 721, and 722 H CDRs and V of SEQ ID NOs: 723, 724, and 725 L those containing CDRs, (lxiv) V of SEQ ID NOs: 730, 731, and 732 H CDRs and V of SEQ ID NOs: 733, 734, and 735 L those containing CDRs, (lxv) V of SEQ ID NOs: 740, 741, and 742 H CDRs and V of SEQ ID NOs: 743, 744, and 745 L those containing CDRs, (lxvi) V of SEQ ID NOs: 750, 751, and 752 H CDRs and V of SEQ ID NOs: 753, 754, and 755 L those containing CDRs, (lxvii) V of SEQ ID NOs: 760, 761, and 762 H CDRs and V of SEQ ID NOs: 763, 764, and 765 L those containing CDRs, (lxviii) V of SEQ ID NOs: 770, 771, and 772 H CDRs and V of SEQ ID NOs: 773, 774, and 775 L those containing CDRs, (lxix) V of SEQ ID NOs: 780, 781, and 782 H CDRs and V of SEQ ID NOs: 783, 784, and 785 L those containing CDRs, (lxx) V of SEQ ID NOs: 790, 791, and 792 H CDRs and V of SEQ ID NOs: 793, 794, and 795 L those containing CDRs, (lxxi) V of SEQ ID NOs: 800, 801, and 802 H CDRs and V of SEQ ID NOs: 803, 804, and 805 L those containing CDRs, (lxxii) V of SEQ ID NOs: 810, 811, and 812 H CDRs and V of SEQ ID NOs: 813, 814, and 815 L It is a specific object of the present invention to provide a use, medicament, composition or method according to any of the foregoing, which is selected from: a) a CDR-containing polypeptide;

[0098] It is a specific object of the present invention to provide an antibody drug conjugate (ADC) as described in any of the foregoing, wherein the ADC comprises an anti-VISTA antibody or antibody fragment that comprises the same CDRs as any one of VSTB92, VSTB56, VSTB95, VSTB103, and VSTB66.

[0099] The antibody drug conjugate (ADC) of any of the preceding claims, wherein the ADC comprises an anti-VISTA antibody or antibody fragment comprising a VH polypeptide and a VL polypeptide, wherein the antibody comprises the following VH polypeptide and VL polypeptide, respectively: (i) V identical to SEQ ID NO: 106 H Polypeptide and V of SEQ ID NO: 108 L those containing polypeptides, (ii) V of SEQ ID NO: 116 HPolypeptide and V of SEQ ID NO: 118 L those containing polypeptides, (iii) V of SEQ ID NO: 126 H Polypeptide and V of SEQ ID NO: 128 L those containing polypeptides, (iv) V of SEQ ID NO: 136 H Polypeptide and V of SEQ ID NO: 138 L those containing polypeptides, (v) V of SEQ ID NO: 146 H Polypeptide and V of SEQ ID NO: 148 L those containing polypeptides, (vi) V of SEQ ID NO: 156 H Polypeptide and V of SEQ ID NO: 158 L those containing polypeptides, (vii) V of SEQ ID NO: 166 H Polypeptide and V of SEQ ID NO: 168 L those containing polypeptides, (viii) V of SEQ ID NO: 176 H Polypeptide and V of SEQ ID NO: 178 L those containing polypeptides, (ix) V of SEQ ID NO: 186 H Polypeptide and V of SEQ ID NO: 188 L those containing polypeptides, (x) V of SEQ ID NO: 196 H Polypeptide and V of SEQ ID NO: 198 L those containing polypeptides, (xi) V of SEQ ID NO: 206 H Polypeptide and V of SEQ ID NO: 208 L those containing polypeptides, (xii) V of SEQ ID NO: 216 H Polypeptide and V of SEQ ID NO: 218 L those containing polypeptides, (xiii) V of SEQ ID NO: 226 H Polypeptide and V of SEQ ID NO: 228 L those containing polypeptides, (xiv) V of SEQ ID NO: 236 H Polypeptide and V of SEQ ID NO: 238L those containing polypeptides, (xv) V of SEQ ID NO: 246 H Polypeptide and V of SEQ ID NO: 248 L those containing polypeptides, (xvi) V of SEQ ID NO: 256 H Polypeptide and V of SEQ ID NO: 258 L those containing polypeptides, (xvii) V of SEQ ID NO: 266 H polypeptide, and V of SEQ ID NO: 268 L those containing polypeptides, (xviii) V of SEQ ID NO: 276 H a polypeptide and a VL polypeptide of SEQ ID NO: 278; (xix) V of SEQ ID NO: 286 H Polypeptide and V of SEQ ID NO: 288 L those containing polypeptides, (xx) V of SEQ ID NO: 296 H Polypeptide and V of SEQ ID NO: 298 L those containing polypeptides, (xxi) V of SEQ ID NO: 306 H polypeptide, and V of SEQ ID NO: 308 L those containing polypeptides, (xxii) V of SEQ ID NO: 316 H Polypeptide and V of SEQ ID NO: 318 L those containing polypeptides, (xxiii) V of SEQ ID NO: 326 H Polypeptide and V of SEQ ID NO: 328 L those containing polypeptides, (xxiv) V of SEQ ID NO: 336 H Polypeptide and V of SEQ ID NO: 338 L those containing polypeptides, (xxv) V of SEQ ID NO: 346 H Polypeptide and V of SEQ ID NO: 348 L those containing polypeptides, (xxvi) V of SEQ ID NO: 356 H Polypeptide and V of SEQ ID NO: 358 Lthose containing polypeptides, (xxvii) V of SEQ ID NO: 366 H Polypeptide and V of SEQ ID NO: 368 L those containing polypeptides, (xxviii) V of SEQ ID NO: 376 H Polypeptide and V of SEQ ID NO: 378 L those containing polypeptides, (xxix) V of SEQ ID NO: 386 H Polypeptide and V of SEQ ID NO: 388 L those containing polypeptides, (xxx) V of SEQ ID NO: 396 H Polypeptide and V of SEQ ID NO: 398 L those containing polypeptides, (xxxi) V of SEQ ID NO: 406 H Polypeptide and V of SEQ ID NO: 408 L those containing polypeptides, (xxxii) V of SEQ ID NO: 416 H Polypeptide and V of SEQ ID NO: 418 L those containing polypeptides, (xxxiii) V of SEQ ID NO: 426 H Polypeptide and V of SEQ ID NO: 428 L those containing polypeptides, (xxxiv) V of SEQ ID NO: 436 H Polypeptide and V of SEQ ID NO: 438 L those containing polypeptides, (xxxv) V of SEQ ID NO: 446 H Polypeptide and V of SEQ ID NO: 448 L those containing polypeptides, (xxxvi) V of SEQ ID NO: 456 H Polypeptide and V of SEQ ID NO: 458 L those containing polypeptides, (xxxvii) V of SEQ ID NO: 466 H Polypeptide and V of SEQ ID NO: 468 L those containing polypeptides, (xxxviii) V of SEQ ID NO: 476 H Polypeptide and V of SEQ ID NO: 478L those containing polypeptides, (xxxix) V of SEQ ID NO: 486 H Polypeptide and V of SEQ ID NO: 488 L those containing polypeptides, (xl) V of SEQ ID NO: 496 H Polypeptide and V of SEQ ID NO: 498 L those containing polypeptides, (xli) V of SEQ ID NO: 506 H Polypeptide and V of SEQ ID NO: 508 L those containing polypeptides, (xlii) V of SEQ ID NO: 516 H Polypeptide and V of SEQ ID NO: 518 L those containing polypeptides, (xliii) V of SEQ ID NO: 526 H Polypeptide and V of SEQ ID NO: 528 L those containing polypeptides, (xliv) V of SEQ ID NO: 536 H polypeptides, and V of SEQ ID NOs: 533, 534, and 535 L those containing polypeptides, (xlv) V of SEQ ID NO: 546 H Polypeptide and V of SEQ ID NO: 548 L those containing polypeptides, (xlvi) V of SEQ ID NO: 556 H Polypeptide and V of SEQ ID NO: 558 L those containing polypeptides, (xlvii) V of SEQ ID NO: 566 H Polypeptide and V of SEQ ID NO: 568 L those containing polypeptides, (xlviii) V of SEQ ID NO: 576 H Polypeptide and V of SEQ ID NO: 578 L those containing polypeptides, (xlix) V of SEQ ID NO: 586 H Polypeptide and V of SEQ ID NO: 588 L those containing polypeptides, (l) V of SEQ ID NO: 596 HPolypeptide and V of SEQ ID NO: 598 L those containing polypeptides, (li) V of SEQ ID NO: 606 H Polypeptide and V of SEQ ID NO: 608 L those containing polypeptides, (lii) V of SEQ ID NO: 616 H Polypeptide and V of SEQ ID NO: 618 L those containing polypeptides, (liii) V of SEQ ID NO: 626 H polypeptide, and V of SEQ ID NO: 628 L those containing polypeptides, (liv) V of SEQ ID NO: 636 H Polypeptide and V of SEQ ID NO: 638 L those containing polypeptides, (lv) V of SEQ ID NO: 646 H polypeptide, and V of SEQ ID NO: 648 L those containing polypeptides, (lvi) V of SEQ ID NO: 656 H Polypeptide and V of SEQ ID NO: 658 L those containing polypeptides, (lvii) V of SEQ ID NO: 666 H Polypeptide and V of SEQ ID NO: 668 L those containing polypeptides, (lviii) V of SEQ ID NO: 676 H Polypeptide and V of SEQ ID NO: 678 L those containing polypeptides, (lix) V of SEQ ID NO: 686 H Polypeptide and V of SEQ ID NO: 688 L those containing polypeptides, (lx) V of SEQ ID NO: 696 H Polypeptide and V of SEQ ID NO: 698 L those containing polypeptides, (lxi) V of SEQ ID NO: 706 H Polypeptide and V of SEQ ID NO: 708 L those containing polypeptides, (lxii) V of SEQ ID NO: 716 HPolypeptide and V of SEQ ID NO: 718 L those containing polypeptides, (lxiii) V of SEQ ID NO: 726 H Polypeptide and V of SEQ ID NO: 728 L those containing polypeptides, (lxiv) V of SEQ ID NO: 736 H Polypeptide and V of SEQ ID NO: 738 L those containing polypeptides, (lxv) V of SEQ ID NO: 746 H Polypeptide and V of SEQ ID NO: 748 L those containing polypeptides, (lxvi) V of SEQ ID NO: 756 H Polypeptide and V of SEQ ID NO: 758 L those containing polypeptides, (lxvii) V of SEQ ID NO: 766 H Polypeptide and V of SEQ ID NO: 768 L those containing polypeptides, (lxviii) V of SEQ ID NO: 776 H Polypeptide and V of SEQ ID NO: 778 L those containing polypeptides, (lxix) V of SEQ ID NO: 786 H Polypeptide and V of SEQ ID NO: 788 L those containing polypeptides, (lxx) V of SEQ ID NO: 796 H Polypeptide and V of SEQ ID NO: 798 L those containing polypeptides, (lxxi) V of SEQ ID NO: 806 H Polypeptide and V of SEQ ID NO: 808 L those containing polypeptides, and (lxxii) V of SEQ ID NO: 816 H Polypeptide and V of SEQ ID NO: 818 L It is a specific object of the present invention to provide ADCs that retain at least 90%, 95%, or 100% sequence identity to an antibody, including the sequence of the polypeptide, and further, wherein the CDRs are unmodified.

[0100] It is a specific object of the present invention to provide a use, agent, composition or method as described in any of the foregoing, wherein the ADC comprises an anti-human VISTA antibody or antibody fragment, and the anti-VISTA antibody or antibody fragment comprises the same variable region as one of VSTB92, VSTB56, VSTB95, VSTB103, and VSTB66.

[0101] It is a specific object of the present invention to provide a use, medicament, composition or method according to any of the foregoing, wherein the ADC optionally comprises an anti-human VISTA antibody or antibody fragment having the CDRs or variable sequences of the antibody of Figure 8, 10 or 12, and wherein the anti-VISTA antibody or antibody fragment comprises a human IgG2 kappa backbone with V234A / G237A / P238S / H268A / V309L / A330S / P331S silencing mutations in the Fc region.

[0102] It is a specific object of the present invention to provide a use, medicament, composition or method according to any of the foregoing, wherein the ADC optionally comprises an anti-human VISTA antibody or antibody fragment having the CDRs or variable sequences of the antibody of Figure 8, 10 or 12, and wherein the anti-VISTA antibody or antibody fragment comprises a human IgG1 / kappa backbone with L234A / L235A silencing mutations in the Fc region.

[0103] It is a specific object of the invention to provide an ADC as described in any of the foregoing, wherein the glucocorticosteroid agonist or linker conjugate is conjugated via its interchain disulfide to an antibody or antibody fragment that specifically binds to a human immune cell-expressed antigen, e.g., an anti-human VISTA antibody or antibody fragment.

[0104] It is a specific object of the present invention to provide a pharmaceutical composition comprising a therapeutically effective amount of at least one antibody drug conjugate (ADC) or steroid agonist or steroid linker as described in any of the foregoing, and a pharmaceutically acceptable carrier.

[0105] It is a specific object of the present invention to provide a composition as described in any of the foregoing that is administrable via injection route, optionally intravenous, intramuscular, intrathecal, or subcutaneous administration.

[0106] It is a specific object of the present invention to provide a composition as described above that is administrable subcutaneously.

[0107] It is a specific object of the present invention to provide a device comprising any of the foregoing glucocorticosteroid agonists, linker conjugates, ADCs, compositions, or agents that provides subcutaneous administration selected from the group consisting of a syringe, an injection device, an infusion pump, an injector pen, a needle-free device, an auto-injector, and a subcutaneous patch delivery system.

[0108] It is a specific object of the present invention to provide a device that delivers a fixed dose of a glucocorticoid receptor agonist or functional derivative thereof to a patient, and optionally further includes instructions informing the patient of the method and dosing regimen of administering the ADC composition contained therein.

[0109] It is a specific object of the present invention to provide a method of treatment and / or prevention comprising administering to a patient in need thereof at least one antibody drug conjugate (ADC) or steroid or composition as described above, wherein said composition may be present in a device as described above.

[0110] It is a specific object of the present invention to provide a method of treatment and / or prophylaxis as described in any of the foregoing for use in the treatment of allergy, autoimmunity, transplantation, gene therapy, inflammation, GVHD, or sepsis in a human subject, or for treating or preventing inflammatory, autoimmune, or allergic side effects associated with any of the foregoing conditions.

[0111] It is a specific object of the present invention to provide a method of treatment and / or prevention as described in any of the foregoing, wherein the patient has a condition selected from rheumatoid arthritis, juvenile idiopathic arthritis, psoriatic arthritis, ankylosing spondylitis, adult Crohn's disease, pediatric Crohn's disease, ulcerative colitis, plaque psoriasis, hidradenitis suppurativa, uveitis, Behcet's disease, spondyloarthropathy, or psoriasis.

[0112] The patient has one or more of the following: (i) chronic, acute, or temporary allergic, inflammatory, or inflammatory conditions, e.g., chronic, acute, temporary, remitting / relapsing; (ii) conditions that are only primarily treatable effectively with high doses of steroids, optionally polymyalgia rheumatica and / or giant cell arteritis, where the patient is or has been treated with optionally high doses of steroids; (iii) conditions with comorbidities that limit steroid use, optionally including diabetes, nonalcoholic steatohepatitis (NASH), morbid obesity, avascular necrosis / osteonecrosis (AVN), glaucoma, steroid-induced hypertension, severe skin fragility, and / or osteoarthritis; (iv) conditions where safe long-term treatments are available but where several months of induction with high dose steroids is desired, optionally where several months of induction with high dose steroids is therapeutically justified, such as AAV, polymyositis, dermatomyositis, lupus, inflammatory lung disease, autoimmune hepatitis, inflammatory bowel disease, immune thrombocytopenia, autoimmune hemolytic anemia, gout patients; (v) Skin conditions requiring short / long term treatment, optionally conditions of uncertain treatment or duration and / or conditions with no effective alternative to steroid administration, optionally other severe immune-mediated skin conditions such as Stevens-Johnson, other severe drug rash conditions, conditions with widespread contact dermatitis, PG, LCV, erythroderma, and the like; (vi) conditions treated with high-dose corticosteroids for exacerbations / recurrences, optionally COPD, asthma, lupus, gout, pseudogout; (vii) immune-mediated neurological disorders such as small fiber neuropathy, MS (subset), chronic inflammatory demyelinating polyneuropathy, myasthenia gravis, and the like; (viii) optionally, hematology / oncology indications where high doses of steroids are therapeutically justified or beneficial; (ix) ophthalmic conditions, optionally uveitis, iritis, scleritis, and the like; (x) conditions associated with permanent or very long-term adrenal insufficiency or secondary adrenal insufficiency, optionally, iatrogenic Addisonian crisis; (xi) conditions often treated with long-term low-dose steroids, optionally lupus, RA, psoriasis, vasculitis, and the like; (xii) It is a specific object of the present invention to provide a method of treatment and / or prevention as defined in any of the foregoing, including in special classes of patients such as pregnant / lactating women, pediatric patients, optionally pediatric patients with growth disorders or cataracts, or any combination of the foregoing.

[0113] It is a particular object of the present invention to provide a method, medicament or use according to any of the foregoing, wherein the patient is further treated with another active agent.

[0114] It is a specific object of the present invention to provide a method of treatment and / or prevention according to any of the foregoing, wherein the patient is further treated with an immunomodulatory antibody or fusion protein selected from an immunoinhibitory antibody or fusion protein targeting one or more of CTLA4, PD-1, PDL-1, LAG-3, TIM-3, BTLA, B7-H4, B7-H3, VISTA, and / or an agonistic antibody or fusion protein targeting one or more of CD40, CD137, OX40, GITR, CD27, CD28, or ICOS.

[0115] It is a specific object of the present invention to provide an ex vivo use of any of the aforementioned ADCs or steroids, wherein immune cells from a patient or donor are contacted with any of the aforementioned ADCs or steroids and then infused into a patient in need thereof, e.g., a patient having one or more of the previously identified conditions.

[0116] It is a specific object of the invention to provide an ADC as described in any of the foregoing, wherein the linker is a positively, negatively, or neutrally charged cleavable peptide, which is optionally esterase cleavable.

[0117] It is a specific object of the present invention to provide any of the aforementioned ADCs, wherein the drug-antibody ratio is in the range of 1:1 to 12:1 or 1:1 to 10:1.

[0118] It is a specific object of the present invention to provide any of the aforementioned ADCs, wherein the drug-antibody ratio is in the range of 2 to 8:1, 4 to 8:1, or 6 to 8:1.

[0119] Drug-Antibody Ratio It is a specific object of the invention to provide an ADC as described in any of the foregoing, wherein the drug-antibody ratio is about 8:1 (n=8) or about 4:1 (n=4).

[0120] It is a specific object of the present invention to provide an ADC as described in any of the foregoing that internalizes one or more of activated or non-activated monocytes, myeloid cells, B cells, NK cells, T cells, CD4 T cells, CD8 T cells, Tregs, mast cells, eosinophils, dendritic cells, mast cells, macrophages, and neutrophils, among other immune cell types.

[0121] It is a specific object of the present invention to provide an ADC as described in any of the foregoing that does not appreciably internalize activated or non-activated B cells.

[0122] It is a specific object of the invention to provide an ADC as described in any of the foregoing that, when administered to a subject in need of treatment, enhances efficacy and / or reduces adverse side effects associated with glucocorticoid receptor agonists compared to the same dose of the anti-inflammatory agent administered in naked (unconjugated) form.

[0123] It is a specific object of the invention to provide an ADC as described in any of the foregoing, wherein the glucocorticoid receptor agonist is conjugated to the antibody or antigen-binding fragment via an interchain disulfide.

[0124] It is a specific object of the present invention to provide an ADC as described in any of the foregoing that comprises an esterase-sensitive linker.

[0125] It is a specific object of the invention to provide an ADC as described in any of the foregoing that comprises a cleavable linker susceptible to one or more of acid-induced cleavage, photo-induced cleavage, peptidase-induced cleavage, esterase-induced cleavage, and disulfide bond cleavage.

[0126] It is a specific object of the invention to provide an ADC as described in any of the foregoing, which comprises a non-cleavable linker that is substantially resistant to one or more of acid-induced cleavage, light-induced cleavage, peptidase-induced cleavage, esterase-induced cleavage, and disulfide bond cleavage.

[0127] It is a specific object of the present invention to provide an ADC as described above, wherein the anti-VISTA antigen-binding fragment comprised in the ADC comprises a Fab, F(ab')2, or scFv antibody fragment.

[0128] It is a specific object of the present invention to provide a method of treatment and / or prevention comprising administering to a patient in need thereof at least one antibody drug conjugate (ADC) or composition, which composition may be present in a device as described in any of the foregoing.

[0129] It is a specific object of the present invention to provide a method of treatment and / or prevention comprising administering to a patient in need thereof at least one antibody drug conjugate (ADC) or composition, which may be present in any of the devices described above, for the treatment of allergy, autoimmunity, transplantation, gene therapy, inflammation, GVHD, or sepsis in a human subject, or for treating or preventing inflammatory, autoimmune, or allergic side effects associated with any of the aforementioned conditions.

[0130] It is a specific object of the present invention to provide a method of treatment and / or prevention comprising administering to a patient in need thereof at least one antibody drug conjugate (ADC) or composition, which composition may be present in any of the devices described above for the treatment of a patient having a condition selected from rheumatoid arthritis, juvenile idiopathic arthritis, psoriatic arthritis, ankylosing spondylitis, adult Crohn's disease, pediatric Crohn's disease, ulcerative colitis, plaque psoriasis, hidradenitis suppurativa, uveitis, Behcet's disease, spondyloarthropathy, or psoriasis.

[0131] The method comprises administering to a patient in need of treatment and / or prevention at least one antibody drug conjugate (ADC) or composition, wherein the composition is selected from the group consisting of one or more of the following: (i) conditions that are only primarily treatable effectively with high doses of steroids, optionally polymyalgia rheumatica and / or giant cell arteritis, where the patient is or has been treated with optionally high doses of steroids; (ii) conditions with comorbidities that limit steroid use, optionally including diabetes, nonalcoholic steatohepatitis (NASH), morbid obesity, avascular necrosis / osteonecrosis (AVN), glaucoma, steroid-induced hypertension, severe skin fragility, and / or osteoarthritis; (iii) conditions where safe long-term treatments are available but where several months of induction with high doses of steroids is desired, optionally where several months of induction with high doses of steroids is therapeutically justified, such as AAV, polymyositis, dermatomyositis, lupus, inflammatory lung disease, autoimmune hepatitis, inflammatory bowel disease, immune thrombocytopenia, autoimmune hemolytic anemia, and gout patients; (iv) Skin conditions requiring short / long term treatment, optionally conditions of uncertain treatment or duration and / or conditions with no effective alternative to steroid administration, optionally other severe immune-mediated skin conditions such as Stevens-Johnson, other severe drug rash conditions, conditions with widespread contact dermatitis, PG, LCV, erythroderma, and the like; (v) conditions treated with high-dose corticosteroids for exacerbations / recurrences, optionally COPD, asthma, lupus, gout, pseudogout; (vi) immune-mediated neurological disorders such as small fiber neuropathy, MS (subset), chronic inflammatory demyelinating polyneuropathy, myasthenia gravis, and the like; (vii) optionally, hematology / oncology indications where high dose steroids are therapeutically justified or beneficial; (viii) ophthalmic conditions, optionally uveitis, iritis, scleritis, and the like; (ix) conditions associated with permanent or very long-term adrenal insufficiency or secondary adrenal insufficiency, optionally, iatrogenic Addisonian crisis; (x) conditions often treated with long-term low-dose steroids, optionally lupus, RA, psoriasis, vasculitis, and the like; and (xi) It is a specific object of the present invention to provide a method of treatment and / or prevention that may be present in any of the devices described above for the treatment of patients, including pregnant / lactating women, pediatric patients, and optionally special classes of patients such as pediatric patients with growth disorders or cataracts.

[0132] It is a specific object of the present invention to provide a method of treatment and / or prevention comprising administering to a patient in need thereof at least one antibody drug conjugate (ADC) or composition, which composition may be present in any of the devices described above for treatment of the patient who is further being treated with another active agent.

[0133] It is a specific object of the present invention to provide a method of treatment and / or prevention comprising administering to a patient in need thereof at least one antibody drug conjugate (ADC) or composition, which composition may be present within any of the aforementioned devices for the treatment of a patient who is further treated with an immunomodulatory antibody or fusion protein optionally selected from immunoinhibitory antibodies or fusion proteins targeting one or more of CTLA4, PD-1, PDL-1, LAG-3, TIM-3, BTLA, B7-H4, B7-H3, VISTA, and / or agonistic antibodies or fusion proteins targeting one or more of CD40, CD137, OX40, GITR, CD27, CD28, or ICOS.

[0134] It is a specific object of the present invention to provide a method of treatment and / or prevention comprising administering to a patient in need thereof at least one antibody drug conjugate (ADC) or composition, which composition may be present in any of the devices described above for the treatment or prevention of acute or chronic inflammation and autoimmune and inflammatory indications related thereto, the condition optionally including severe asthma, giant cell arteritis, ANKA vasculitis, and IBD (colitis and Crohn's disease).

[0135] It is a specific object of the present invention to provide a method of treatment and / or prevention comprising administering to a patient in need thereof at least one antibody drug conjugate (ADC) or composition, which composition may be present in any of the aforementioned devices for the treatment and prevention of a condition selected from rheumatoid arthritis, juvenile idiopathic arthritis, psoriatic arthritis, ankylosing spondylitis, adult Crohn's disease, pediatric Crohn's disease, ulcerative colitis, plaque psoriasis, hidradenitis suppurativa, uveitis, Behcet's disease, spondyloarthropathy, or psoriasis.

[0136] It is a specific object of the present invention to provide a method for effecting internalization of a steroid into one or more of myeloid cells, T cells, CD4 T cells, CD8 T cells, Tregs, NK cells, neutrophils, monocytes, B cells, NK cells, myeloid cells, dendritic cells, eosinophils, mast cells, and macrophages, among other immune cell types, comprising administering to a subject or contacting the cells ex vivo with any of the ADCs described above.

[0137] It is a specific object of the present invention to provide a method for effecting internalization of a steroid into one or more of myeloid cells, NK cells, B cells, T cells, CD4 T cells, CD8 T cells, Tregs, NK cells, neutrophils, monocytes, myeloid cells, dendritic cells, eosinophils, mast cells, and macrophages, comprising administering to a subject or contacting the cells ex vivo with any of the ADCs described above, which is accomplished ex vivo, wherein a purified or enriched composition comprising immune cells, or one or more specific types of immune cells selected from cells, CD4 T cells, CD8 T cells, Tregs, NK cells, neutrophils, monocytes, myeloid cells, mast cells, dendritic cells, eosinophils, and macrophages, among other immune cell types, is contacted ex vivo with any of the ADCs described above and thereafter introduced into a patient in need thereof.

[0138] It is a specific object of the present invention to provide a method for effecting internalization of a steroid into one or more of myeloid cells, NK cells, B cells, T cells, CD4 T cells, CD8 T cells, Tregs, NK cells, neutrophils, monocytes, mast cells, myeloid cells, dendritic cells, eosinophils, mast cells, and macrophages, comprising administering to a subject in need of treatment an ADC as described above, wherein the method comprises administering to the subject or contacting the cells ex vivo with an ADC according to any of the foregoing methods for treating an inflammatory or autoimmune or allergic condition involving any one or more of myeloid cells, NK cells, B cells, T cells, Tregs, NK cells, neutrophils, monocytes, myeloid cells, dendritic cells, mast cells, eosinophils, and macrophages. [Brief explanation of the drawings]

[0139] [Figure 1] Peptide mapping of the control VISTA antibody 767-IgG1.3 by trypsin digestion is shown. The determined sequence of 767-IgG1.3 with identified tryptic peptides are underlined in (A) the light chain (85.6% coverage) and (B) the heavy chain (76.1% coverage). [Figure 2] The determined sequence of 767-IgG1.3 using Lys-C digestion is shown, with Lys-C peptides underlined in (A) the light chain (63.3% coverage) and (B) the heavy chain (76.3% coverage). [Figure 3] Included are the results of binding experiments confirming that synthetic control antibodies 767-IgG1.3 and INX 200 exhibit opposite pH-dependent binding properties. [Figure 4A] Included are the results of binding studies revealing that DAR 8 conjugation with linker A does not affect VISTA binding to INX200. [Figure 4B] Included are the results of binding studies revealing that DAR 8 conjugation with Linker A does not affect VISTA binding to INX201. [Figure 4C]1 includes the results of binding studies revealing that DAR 8 conjugation with Linker A does not affect VISTA binding to 767-IgG1.3. [Figure 5] Results from a ConA experiment in which female hVISTA knock-in animals were dosed with different naked and Dex-conjugated anti-VISTA antibodies to detect G-CSF changes 6 hours post-ConA in peripheral blood. Plasma concentrations (SEM; n=5 / group) measured using a mouse 7-plex (dosages: Dex-0.2 = 0.2 mg / Kg, Dex-2 = 2 mg / Kg, INX210 and INX210A at 10 mg / Kg [INX210A provided a dex payload of 0.2 mg / kg]). [Figure 6] Figure 1 contains the results of a ConA study in which male hVISTA knock-in animals were dosed with different naked and Dex-conjugated anti-VISTA antibodies. In the experiment shown, cytokine changes in peripheral blood 6 hours after ConA. Plasma concentrations (SEM; n=10 / group, ordinary one-way ANOVA compared to the ConA-only group) measured using a mouse 7-plex (dosage: Dex at 0.2 or 5 mg / kg, INX210 and INX210A at 10 mg / kg). [Figure 7] Animals were dosed with different naked and Dex-conjugated anti-VISTA antibodies, and cytokine changes were detected in peripheral blood 6 hours post-ConA. Plasma concentrations were measured using an ELISA assay (SD; n=6 / group; one-way ANOVA compared to the ConA-only group) (dosage: Dex at 0.02, 0.2, or 2 mg / kg, INX200A at 10, 5, and 1 mg / kg). [Figure 8] Includes sequences and sequence legends for the variable heavy and light and constant regions of INX200, INX201, and INX210. [Figure 9] Exemplary budenoside derivatives are shown. [Figure 10A]A sequence listing is included, including the CDRs, variable heavy and light sequences, framework sequences, and constant domains, and epitope information for exemplary anti-human VISTA antibodies VSTB49 to VSTB116, which have short serum half-lives in rodents and primates at physiological conditions (≈pH 7.5). [Figure 10B] A sequence listing is included, including the CDRs, variable heavy and light sequences, framework sequences, and constant domains, and epitope information for exemplary anti-human VISTA antibodies VSTB49 to VSTB116, which have short serum half-lives in rodents and primates at physiological conditions (≈pH 7.5). [Figure 10C] A sequence listing is included, including the CDRs, variable heavy and light sequences, framework sequences, and constant domains, and epitope information for exemplary anti-human VISTA antibodies VSTB49 to VSTB116, which have short serum half-lives in rodents and primates at physiological conditions (≈pH 7.5). [Figure 10D] A sequence listing is included, including the CDRs, variable heavy and light sequences, framework sequences, and constant domains, and epitope information for exemplary anti-human VISTA antibodies VSTB49 to VSTB116, which have short serum half-lives in rodents and primates at physiological conditions (≈pH 7.5). [Figure 10E] A sequence listing is included, including the CDRs, variable heavy and light sequences, framework sequences, and constant domains, and epitope information for exemplary anti-human VISTA antibodies VSTB49 to VSTB116, which have short serum half-lives in rodents and primates at physiological conditions (≈pH 7.5). [Figure 10F] A sequence listing is included, including the CDRs, variable heavy and light sequences, framework sequences, and constant domains, and epitope information for exemplary anti-human VISTA antibodies VSTB49 to VSTB116, which have short serum half-lives in rodents and primates at physiological conditions (≈pH 7.5). [Figure 10G]A sequence listing is included, including the CDRs, variable heavy and light sequences, framework sequences, and constant domains, and epitope information for exemplary anti-human VISTA antibodies VSTB49 to VSTB116, which have short serum half-lives in rodents and primates at physiological conditions (≈pH 7.5). [Figure 10H] A sequence listing is included, including the CDRs, variable heavy and light sequences, framework sequences, and constant domains, and epitope information for exemplary anti-human VISTA antibodies VSTB49 to VSTB116, which have short serum half-lives in rodents and primates at physiological conditions (≈pH 7.5). [Figure 10I] A sequence listing is included, including the CDRs, variable heavy and light sequences, framework sequences, and constant domains, and epitope information for exemplary anti-human VISTA antibodies VSTB49 to VSTB116, which have short serum half-lives in rodents and primates at physiological conditions (≈pH 7.5). [Figure 10J] A sequence listing is included, including the CDRs, variable heavy and light sequences, framework sequences, and constant domains, and epitope information for exemplary anti-human VISTA antibodies VSTB49 to VSTB116, which have short serum half-lives in rodents and primates at physiological conditions (≈pH 7.5). [Figure 10K] A sequence listing is included, including the CDRs, variable heavy and light sequences, framework sequences, and constant domains, and epitope information for exemplary anti-human VISTA antibodies VSTB49 to VSTB116, which have short serum half-lives in rodents and primates at physiological conditions (≈pH 7.5). [Figure 10L] A sequence listing is included, including the CDRs, variable heavy and light sequences, framework sequences, and constant domains, and epitope information for exemplary anti-human VISTA antibodies VSTB49 to VSTB116, which have short serum half-lives in rodents and primates at physiological conditions (≈pH 7.5). [Figure 10M]A sequence listing is included, including the CDRs, variable heavy and light sequences, framework sequences, and constant domains, and epitope information for exemplary anti-human VISTA antibodies VSTB49 to VSTB116, which have short serum half-lives in rodents and primates at physiological conditions (≈pH 7.5). [Figure 10N] A sequence listing is included, including the CDRs, variable heavy and light sequences, framework sequences, and constant domains, and epitope information for exemplary anti-human VISTA antibodies VSTB49 to VSTB116, which have short serum half-lives in rodents and primates at physiological conditions (≈pH 7.5). [Figure 10O] A sequence listing is included, including the CDRs, variable heavy and light sequences, framework sequences, and constant domains, and epitope information for exemplary anti-human VISTA antibodies VSTB49 to VSTB116, which have short serum half-lives in rodents and primates at physiological conditions (≈pH 7.5). [Figure 10P] A sequence listing is included, including the CDRs, variable heavy and light sequences, framework sequences, and constant domains, and epitope information for exemplary anti-human VISTA antibodies VSTB49 to VSTB116, which have short serum half-lives in rodents and primates at physiological conditions (≈pH 7.5). [Figure 10Q] A sequence listing is included, including the CDRs, variable heavy and light sequences, framework sequences, and constant domains, and epitope information for exemplary anti-human VISTA antibodies VSTB49 to VSTB116, which have short serum half-lives in rodents and primates at physiological conditions (≈pH 7.5). [Figure 10R] A sequence listing is included, including the CDRs, variable heavy and light sequences, framework sequences, and constant domains, and epitope information for exemplary anti-human VISTA antibodies VSTB49 to VSTB116, which have short serum half-lives in rodents and primates at physiological conditions (≈pH 7.5). [Figure 10S]A sequence listing is included, including the CDRs, variable heavy and light sequences, framework sequences, and constant domains, and epitope information for exemplary anti-human VISTA antibodies VSTB49 to VSTB116, which have short serum half-lives in rodents and primates at physiological conditions (≈pH 7.5). [Figure 10T] A sequence listing is included, including the CDRs, variable heavy and light sequences, framework sequences, and constant domains, and epitope information for exemplary anti-human VISTA antibodies VSTB49 to VSTB116, which have short serum half-lives in rodents and primates at physiological conditions (≈pH 7.5). [Figure 10U] A sequence listing is included, including the CDRs, variable heavy and light sequences, framework sequences, and constant domains, and epitope information for exemplary anti-human VISTA antibodies VSTB49 to VSTB116, which have short serum half-lives in rodents and primates at physiological conditions (≈pH 7.5). [Figure 10V] A sequence listing is included, including the CDRs, variable heavy and light sequences, framework sequences, and constant domains, and epitope information for exemplary anti-human VISTA antibodies VSTB49 to VSTB116, which have short serum half-lives in rodents and primates at physiological conditions (≈pH 7.5). [Figure 10W] A sequence listing is included, including the CDRs, variable heavy and light sequences, framework sequences, and constant domains, and epitope information for exemplary anti-human VISTA antibodies VSTB49 to VSTB116, which have short serum half-lives in rodents and primates at physiological conditions (≈pH 7.5). [Figure 10X] A sequence listing is included, including the CDRs, variable heavy and light sequences, framework sequences, and constant domains, and epitope information for exemplary anti-human VISTA antibodies VSTB49 to VSTB116, which have short serum half-lives in rodents and primates at physiological conditions (≈pH 7.5). [Figure 10Y]A sequence listing is included, including the CDRs, variable heavy and light sequences, framework sequences, and constant domains, and epitope information for exemplary anti-human VISTA antibodies VSTB49 to VSTB116, which have short serum half-lives in rodents and primates at physiological conditions (≈pH 7.5). [Figure 10Z] A sequence listing is included, including the CDRs, variable heavy and light sequences, framework sequences, and constant domains, and epitope information for exemplary anti-human VISTA antibodies VSTB49 to VSTB116, which have short serum half-lives in rodents and primates at physiological conditions (≈pH 7.5). [Figure 10AA] A sequence listing is included, including the CDRs, variable heavy and light sequences, framework sequences, and constant domains, and epitope information for exemplary anti-human VISTA antibodies VSTB49 to VSTB116, which have short serum half-lives in rodents and primates at physiological conditions (≈pH 7.5). [Figure 10BB] A sequence listing is included, including the CDRs, variable heavy and light sequences, framework sequences, and constant domains, and epitope information for exemplary anti-human VISTA antibodies VSTB49 to VSTB116, which have short serum half-lives in rodents and primates at physiological conditions (≈pH 7.5). [Figure 10CC] A sequence listing is included, including the CDRs, variable heavy and light sequences, framework sequences, and constant domains, and epitope information for exemplary anti-human VISTA antibodies VSTB49 to VSTB116, which have short serum half-lives in rodents and primates at physiological conditions (≈pH 7.5). [Figure 10DD] A sequence listing is included, including the CDRs, variable heavy and light sequences, framework sequences, and constant domains, and epitope information for exemplary anti-human VISTA antibodies VSTB49 to VSTB116, which have short serum half-lives in rodents and primates at physiological conditions (≈pH 7.5). [Figure 10EE]A sequence listing is included, including the CDRs, variable heavy and light sequences, framework sequences, and constant domains, and epitope information for exemplary anti-human VISTA antibodies VSTB49 to VSTB116, which have short serum half-lives in rodents and primates at physiological conditions (≈pH 7.5). [Figure 10FF] A sequence listing is included, including the CDRs, variable heavy and light sequences, framework sequences, and constant domains, and epitope information for exemplary anti-human VISTA antibodies VSTB49 to VSTB116, which have short serum half-lives in rodents and primates at physiological conditions (≈pH 7.5). [Figure 10GG] A sequence listing is included, including the CDRs, variable heavy and light sequences, framework sequences, and constant domains, and epitope information for exemplary anti-human VISTA antibodies VSTB49 to VSTB116, which have short serum half-lives in rodents and primates at physiological conditions (≈pH 7.5). [Figure 10HH] A sequence listing is included, including the CDRs, variable heavy and light sequences, framework sequences, and constant domains, and epitope information for exemplary anti-human VISTA antibodies VSTB49 to VSTB116, which have short serum half-lives in rodents and primates at physiological conditions (≈pH 7.5). [Figure 10II] A sequence listing is included, including the CDRs, variable heavy and light sequences, framework sequences, and constant domains, and epitope information for exemplary anti-human VISTA antibodies VSTB49 to VSTB116, which have short serum half-lives in rodents and primates at physiological conditions (≈pH 7.5). [Figure 10JJ] A sequence listing is included, including the CDRs, variable heavy and light sequences, framework sequences, and constant domains, and epitope information for exemplary anti-human VISTA antibodies VSTB49 to VSTB116, which have short serum half-lives in rodents and primates at physiological conditions (≈pH 7.5). [Figure 11A] Exemplary steroid structures include those disclosed in Example 3. [Figure 11B] Exemplary steroid structures include those disclosed in Example 3. [Figure 11C] Exemplary steroid structures include those disclosed in Example 3. [Figure 12A] Included are sequences of exemplary anti-VISTA antibodies and control antibodies disclosed in the Examples. [Figure 12B] Included are sequences of exemplary anti-VISTA antibodies and control antibodies disclosed in the Examples. [Figure 12C] Included are sequences of exemplary anti-VISTA antibodies and control antibodies disclosed in the Examples. [Figure 13] Binding studies of INX200 and 767-IgG1.3 versus human IgG1si. Median fluorescence intensity measured on monocytes incubated with serial dilutions (0-333 nM) of the tested antibodies; dashed black line corresponds to autofluorescence of unstained cells; n=1. [Figure 14] Shown is the percentage of anti-VISTA antibody (INX200) internalized by immune cells. The intracellular pool of cell-bound antibody was plotted over a 60-minute time course. For each data point, fluorescence was normalized to the fluorescence of INX200 at time 0 minutes. Mean ± SD n=2 donors. [Figure 15] Results from an experiment assessing the internalization rate of the INX200 antibody are included. The internalization rate of the INX200 antibody was assessed in monocytes over a 60-minute time course. Anti-CD45 antibody was not internalized at any time point. Shown as mean ± SD, n=2 donors. [Figure 16] Includes a PK study of INX200, INX200A vs. human IgG1. Plasma concentrations of antibodies at annotated time points in hVISTA KI mice (SD; n=5 / group). [Figure 17] Includes PK study of 767-IgG1.3, 767-IgG1.3A vs. human IgG1. Plasma concentrations of antibodies at annotated time points in hVISTA KI mice (SD; n=5 / group). [Figure 18]Included are the results of experiments evaluating the efficacy of ADC conjugates according to the present invention. The experiments assessed FKBP5 transcription activation in peritoneal resident macrophages and splenic monocytes after treatment with Dex (left) and the ADC INX201J (right). Dex (left) effects were assessed 4 and 24 hours after a single intraperitoneal (ip) injection at 2 mg / kg. ADC (right) effects were analyzed 24, 48, 72, and 96 hours after a single i.p. injection at 10 mg / kg, delivering a GC payload of 0.2 mg / kg. FKBP5 transcription levels were measured by real-time PCR and presented as Log2 fold change versus the PBS control group. Four mice per group were pooled together to generate sufficient material for RNA preparation. [Figure 19] Results from in vivo experiments are included, demonstrating that Dex treatment prevents ex vivo induction of inflammatory cytokines in PRM. Dex effects were assessed 2 hours after a single intraperitoneal injection at 2 mg / kg. IL-6 and TNFα were assessed in cell supernatants (collected at 1 hour) using a mouse 32-plex (n = 4 mice / group; unpaired T-test). [Figure 20] Results from experiments evaluating the in vivo effects of INX201J or Dex treatment on TNFα in PRM are included. The results show that INX201J or Dex treatment prevents ex vivo induction of TNFα in PRM. In these experiments, Dex effects were evaluated 2 hours after a single intraperitoneal injection at 2 and 0.2 mg / kg. INX201J effects were evaluated 1 day (d-1), 2 days (d-2), and 4 days (d-4) after injection at 10 mg / kg (equivalent to a 0.2 mg / kg payload). Cell supernatants were collected at 2 hours. TNFα was measured using ELISA (n = 4 mice / group; ordinary one-way ANOVA compared with the PBS-only group). [Figure 21]This section contains the results of an experiment evaluating the long-term effects of exemplary ADCs according to the invention. The results show that all tested ADCs induced long-term effects on the ex vivo induction of TNFα and IL-6 in PRM. Dex effects were evaluated 2 hours after a single intraperitoneal injection at 2 mg / kg. INX201J, INX231J, INX234J, and INX240J effects were evaluated 4 days (-4) and 7 days (-7) after a single intraperitoneal injection at 10 mg / kg. Cell supernatants were collected at 2 hours. TNFα and IL-6 were measured using ELISA (n=4 mice / group; ordinary one-way ANOVA compared to the PBS-only group). [Figure 22] This article contains the results of experiments evaluating the efficacy of exemplary ADC conjugates according to the invention, namely, INX231J, INX234J, and INX240J. The results show that the INX231J, INX234J, and INX240J ADCs have comparable efficacy in preventing ex vivo induction of TNFα and IL-6 in PRM. Dex efficacy was assessed 2 hours after a single intraperitoneal injection at 2 mg / kg. INX231J, INX234J, and INX240J efficacy was assessed 7 days after a single intraperitoneal injection at 10, 3, or 1 mg / kg (equivalent to GC payloads of 0.2, 0.06, and 0.02 mg / kg). Cell supernatants were collected at 2 hours. TNFα and IL-6 were measured using ELISA (see Methods section) (n = 4 mice / group, except for the PBS group n = 1 due to technical reasons; ordinary one-way ANOVA compared with the PBS only group). [Figure 23]Experiments were included to demonstrate that the potency of INX201J, INX201P, INX231J, INX234J, and INX240J ADCs was comparable in preventing ex vivo induction of TNFα and IL-6 in PRM. The effects of INX201J, INX201P, INX231J, INX234J, INX240J, and Dex were assessed 7 days after a single intraperitoneal injection. The ADCs were administered at 10 mg / kg (0.2 mg / kg GC payload) and Dex at 2 mg / kg. Cell supernatants were collected at 2 hours. TNFα and IL-6 were measured using ELISA (n = 4 mice / group, except for the PBS and Dex group, which contained n = 3 due to technical reasons; ordinary one-way ANOVA compared to the PBS-only group). [Figure 24] The INX201J, INX231P, INX234P, and INX240P ADCs are equally effective in preventing ex vivo induction of TNFα in PRM. ADC efficacy was assessed 7 days after a single intraperitoneal injection. ADCs were administered at 10 mg / Kg (0.2 mg / Kg GC payload). Cell supernatants were collected at 2 hours. TNFα was measured using ELISA (see Methods section) (n=4 mice / group; ordinary one-way ANOVA compared with PBS-only group, SEM). [Figure 25] INX231P, INX231R, INX233P, and INX234P are equally effective in preventing ex vivo induction of TNFα and IL-6 in PRM. ADC efficacy was assessed 7 days after a single intraperitoneal injection. ADCs were administered at 10 mg / Kg (0.2 mg / Kg GC payload). Cell supernatants were collected at 24 hours. TNFα and IL-6 were measured using ELISA (see Methods section) (n=4 mice / group; ordinary one-way ANOVA compared with PBS-only group, SEM). [Figure 26]Efficacy evaluation of GC-linker payloads INX R, INX O, INX S, INX V, and INX W versus INX P conjugated to INX231 in preventing ex vivo induction of TNFα and IL-6 in PRM. ADC efficacy was evaluated 7 days after a single intraperitoneal injection. ADCs were administered with a GC payload of 0.2 mg / kg. Cell supernatants were collected at 24 hours. TNFα and IL-6 were measured using ELISA (see Methods section) (n=4 mice / group; ordinary one-way ANOVA compared with PBS-only group, SEM). [Figure 27] Efficacy evaluation of GC payloads INX231S, INX231V, and INX231W versus INX231P in inducing FKBP5 transcription in PRM. ADC efficacy was assessed 1, 7, and 14 days after a single intraperitoneal injection. ADCs were administered with a GC payload of 0.2 mg / kg. FKBP5 expression was measured by quantitative real-time PCR and presented as Log2 fold change versus the PBS control group (n=4 mice / group; ordinary one-way ANOVA compared with the PBS-only group, SEM). [Figure 28] Efficacy evaluation of GC payloads INX231S, INX231V, and INX231W versus INX231P in preventing ex vivo induction of TNFα and IL-6 in PRM. ADC efficacy was evaluated 1, 7, and 14 days after a single intraperitoneal injection. ADCs were administered with a GC payload of 0.2 mg / Kg. Cell supernatants were collected at 24 hours. TNFα and IL-6 were measured using ELISA (see Methods section) (n=4 mice / group; ordinary one-way ANOVA compared with PBS-only group, SEM). [Figure 29]Efficacy evaluation of GC payloads INX234A3, INX234A4, INX234T, INX201L, and INX231S in inducing FKBP5 transcription in peritoneal resident macrophages (top row) and splenocytes (bottom row). ADC efficacy was evaluated 1, 7, and 14 days after a single intraperitoneal injection. ADCs were administered at a GC payload of 0.2 mg / kg. FKBP5 expression was measured by quantitative real-time PCR and presented as Log2 fold change versus the PBS control group (n=4 mice / group; ordinary one-way ANOVA, SEM compared with the PBS-only group). [Figure 30] Efficacy evaluation of GC payloads INX234A3, INX234A4, INX234T, INX201L, and INX231S in preventing ex vivo induction of TNFα and IL-6 in PRM. ADC efficacy was evaluated 1, 7, and 14 days after a single intraperitoneal injection. ADCs were administered at a GC payload of 0.2 mg / Kg. Cell supernatants were collected at 24 hours. TNFα and IL-6 were measured using ELISA (see Methods section) (n=4 mice / group; ordinary one-way ANOVA compared with PBS-only group, SEM). [Figure 31] Efficacy evaluation of GC payloads INX234V, INX234A5, and INX234A11 in inducing FKBP5 transcription in peritoneal resident macrophages. ADC efficacy was evaluated 7 and 14 days after a single intraperitoneal injection. ADCs were administered with a GC payload of 0.2 mg / kg. FKBP5 expression was measured by quantitative real-time PCR and presented as Log2 fold change versus the PBS control group (n=4 mice / group; ordinary one-way ANOVA, SEM compared with the PBS-only group). [Figure 32] Efficacy evaluation of GC payloads INX234V, INX234A5, and INX234A11 in preventing ex vivo induction of TNFα and IL-6 in PRM. ADC efficacy was assessed 14 days after a single intraperitoneal injection, and ADC TNFα and IL-6 were measured using ELISA (see Methods section) (n=4 mice / group; ordinary one-way ANOVA compared to PBS-only group, SEM). [Figure 33]Efficacy evaluation of GC payloads INX234V, INX231A7, INX231A12, and INX231A23 in inducing FKBP5 transcription in peritoneal resident macrophages. ADC efficacy was evaluated 7 and 21 days after a single intraperitoneal injection. ADCs were administered with a GC payload of 0.2 mg / kg, except for INX231A7, which was administered with a payload of 0.08 mg / kg. FKBP5 expression was measured by quantitative real-time PCR and presented as Log2 fold change versus the PBS control group (n = 4 mice / group; ordinary one-way ANOVA, SEM compared with the PBS-only group). [Figure 34] Efficacy evaluation of GC payloads INX234V, INX231A7, INX231A12, and INX231A23 in preventing ex vivo induction of TNFα and IL-6 in PRM. ADC efficacy was evaluated 7, 14, and 21 days after a single intraperitoneal injection. ADCs were administered with a GC payload of 0.2 mg / Kg. Cell supernatants were collected at 24 hours. TNFα and IL-6 were measured using ELISA (see Methods section) (n=4 mice / group; ordinary one-way ANOVA compared with PBS-only group, SEM). [Figure 35] Changes in IL-12p40 in peripheral blood at 2 hours (left) and 4 hours (right) after LPS. Plasma concentrations measured using a mouse multiplex. Doses: Dex (squares) were administered 2 hours before LPS stimulation at 0.02, 0.2, 2, and 5 mg / kg, and INX201J (circles) was administered 2 hours or 17 hours before LPS injection at 10 mg / kg, providing a GC of 0.2 mg / kg. The PBS-only group (gray filled triangles) represents baseline cytokine levels in the absence of stimulation. PBS + LPS (black filled triangles) (SEM; n = 5 / group unless technical failure excluded from analysis; ordinary one-way ANOVA compared with the PBS + LPS group). [Figure 36]Cytokine changes in peripheral blood 2 hours after LPS. Plasma concentrations measured using a mouse 5-plex. Doses: Dex was administered 2 hours before LPS stimulation at 0.002, 0.02, 0.2, or 2 mg / kg (squares) or 17 hours before LPS at 2 mg / kg (solid triangles). INX201J (circles) was administered 17 hours before LPS injection at GC payloads of 0.02, 0.06, or 0.2 mg / kg. The PBS-only group (gray filled triangles) represents baseline cytokine levels in the absence of stimulation. PBS + LPS (solid triangles) (SEM; n = 5 / group unless technical failure excluded from analysis; ordinary one-way ANOVA compared with the PBS + LPS group). [Figure 37] Changes in TNFα in peripheral blood 2 hours after LPS. TNFα plasma concentrations were measured using ELISA. Administration: Dex was administered 2 hours before LPS stimulation at 0.2 and 2 mg / kg (squares), and INX201J (circles) was administered 17 hours before LPS injection at GC payloads of 0.06 and 0.2 mg / kg. The PBS group (black triangles) received PBS 2 hours before LPS. The IgG1siJ (G1siJ) group (triangles) received human IgG1 silently conjugated to GC at a payload of 0.2 mg / kg 17 hours before LPS. (SEM; n = 5 / group unless technical failure excluded from analysis; ordinary one-way ANOVA compared with the PBS group). [Figure 38] Changes in TNFα 2 hours after LPS in peripheral blood. TNFα plasma concentrations were measured by ELISA. Administration: Dex was administered 2 hours before LPS stimulation at 0.2 and 2 mg / kg (squares), and INX201J (circles) and INX201N (inverted triangles) were administered 17 hours before LPS injection at a GC payload of 0.2 mg / kg. The PBS group received PBS 2 hours before LPS (solid triangles). (SEM; n=5 / group unless technical failure excluded from analysis; ordinary one-way ANOVA compared with the PBS group). [Figure 39]Changes in TNFα (left) and IL-12p40 (right) in peripheral blood 2 hours after LPS are shown. Cytokine plasma concentrations were measured by ELISA. Treatment: PBS (filled circles), INX201J (squares), INX231J (triangles), INX234J (diamonds), and INX201P (inverted triangles) were administered 17 hours before LPS injection at a GC payload of 0.2 mg / kg (SEM; n=5 / group; ordinary one-way ANOVA compared to the PBS group). [Figure 40] Changes in TNFα (left) and IL-12p40 (right) in peripheral blood 2 hours after LPS are shown. Cytokine plasma concentrations were measured by ELISA. Administration: PBS (filled triangles), INX201J (circles), INX201O (squares), and INX201P (diamonds) were administered 17 hours before LPS injection at a GC payload of 0.2 mg / kg (SEM; n=5 / group unless technical failure excluded from analysis; ordinary one-way ANOVA compared to the PBS group). [Figure 41] Changes in TNFα (right) and IL-12p40 (left) in peripheral blood 2 hours after LPS are shown. Cytokine plasma concentrations were measured by ELISA. Treatment: PBS, INX201J (circles), INX201O (squares), and INX201P (diamonds) were administered 17 hours before LPS injection at a GC payload of 0.2 mg / kg (SEM; n=5 / group unless technical failure excluded from analysis; ordinary one-way ANOVA compared to the PBS group (filled triangles)). [Figure 42] Changes in TNFα (right) and IL-12p40 (left) in peripheral blood 2 hours after LPS are shown. Cytokine plasma concentrations were measured by ELISA. All ADCs and PBS were administered 20 hours before LPS injection at a GC payload of 0.2 mg / kg (INX231P (squares), INX231R (triangles), INX233P (diamonds)) (SEM; n=5 / group unless technical failure excluded from analysis; ordinary one-way ANOVA compared with the PBS group (filled circles)). [Figure 43]Changes in TNFα (right) and IL-12p40 (left) in peripheral blood 2 hours after LPS are shown. Cytokine plasma concentrations were measured by ELISA. All ADCs and PBS were administered 20 hours before LPS injection at a GC payload of 0.2 mg / kg (INX231P (filled squares), INX231R (filled triangles), INX201O (filled diamonds), INX231S (circles), INX231V (squares), INX231W (triangles)) (SEM; n = 4 / group except for INX231S, for which two technical failures excluded it from the analysis; ordinary one-way ANOVA compared to the PBS group (filled circles) showed non-significant data). [Figure 44] Figure 1 shows FKBP5 transcription activation after ADC treatment in peritoneal residents 4 days after ADC treatment. ADCs were injected intraperitoneally on day 0, each delivering a GC payload of 0.2 mg / Kg. PRMs were isolated on day 3. FKBP5 transcription levels were measured by real-time PCR and presented as Log2 fold change versus the PBS control group (SEM, ordinary one-way ANOVA compared to the PBS group, n=4). [Figure 45] Changes in TNFα (right) and IL-12p40 (left) in peripheral blood 2 hours after LPS. Cytokine plasma concentrations were measured by ELISA. All ADCs and PBS were administered 20 hours before LPS injection at a GC payload of 0.2 mg / kg (SEM; n=5 / group except for INX234P, INX234A4, and INX234T, for which one technical failure was recorded per group; ordinary one-way ANOVA compared with the PBS group). [Figure 46] Changes in TNFα (right) and IL-12p40 (left) 2 hours after LPS in peripheral blood. Cytokine plasma concentrations were measured by ELISA. All ADCs and PBS were administered 20 hours before LPS injection at a GC payload of 0.2 mg / kg (INX234V (filled squares), INX234A5 (filled triangles), INX234A11 (filled diamonds)) (SEM; n=5 / group; ordinary one-way ANOVA compared to the PBS (filled circles) group). [Figure 47]Changes in TNFα (right) and IL-12p40 (left) 2 hours after LPS in peripheral blood. Cytokine plasma concentrations were measured by ELISA. All ADCs and PBS were administered 20 hours before LPS injection at a GC payload of 0.2 mg / kg, except for INX231A7, which was administered at a payload of 0.08 mg / kg (INX234V (filled squares), INX231A7 (filled triangles), INX231A12 (filled diamonds), INX231A23 (circles), INX234A1 (squares), INX234A13 (triangles)). (SEM; n = 5 / group; ordinary one-way ANOVA compared to the PBS group). [Figure 48] Changes in TNFα (right) and IL-12p40 (left) in peripheral blood 2 hours after LPS. Cytokine plasma concentrations were measured by ELISA. All ADCs and PBS were administered 20 hours before LPS injection at a GC payload of 0.2 mg / kg (SEM; except for one sample in the PBS, INX234P, INX201V groups that had to be censored, and two samples in the INX234A9 group for technical reasons; n=5 / group; ordinary one-way ANOVA compared to the PBS group). [Figure 49] This figure shows the results of an experiment to detect VISTA expression on different cells. As shown, VISTA is highly expressed in liver endothelial cells. CD45-CD31+ non-immune endothelial cells isolated from the liver of hVISTA knock-in mice were stained with anti-human VISTA (red line, shifted to the right) or unstained (solid gray). [Figure 50]This section contains the results of an experiment to detect FKBP5 transcriptional activation after INX201J injection in the adrenal gland, brain, liver, and spleen. As indicated, INX201J effects were measured 20 hours after a single intraperitoneal injection at 0.3, 3, or 10 mg / kg (delivering payloads of 0.006, 0.06, and 0.2 mg / kg, respectively). Dex effects were measured 2 hours after a single intraperitoneal injection at 0.2 or 2 mg / kg. FKBP5 transcription levels were measured by real-time PCR and presented as Log2 fold change versus the mean of the PBS control group (n = 4 mice / group, ordinary one-way ANOVA compared with the PBS-only group). [Figure 51] INX-SM-3, INX-SM-4, and INX-SM-1 inhibit IL-1β (left) and IL-6 (right) production. Cytokine levels were measured at 24 h for human PBMCs incubated with 1 ng / mL LPS and serial dilutions (1000–1 nM) of steroid payload; <1 nM is the no treatment control plotted on the x-axis on a logarithmic scale; n = 1 donor; standard deviations are plotted from technical duplicates. [Figure 52] INX-SM-1, INX-SM-3, INX-SM-4, and INX-SM-6 inhibit IL-1β production. Cytokine levels were measured at 24 hours for human PBMCs incubated with 1 ng / mL LPS and serial dilutions (1000–1 nM) of steroid payload; <1 nM was used as the no treatment control plotted on the x-axis on a logarithmic scale; n = 1 donor; standard deviations were plotted from technical duplicates. [Figure 53] INX-SM-9, INX-SM-31, and INX-SM-35 inhibit IL-1β (top) and IL-6 (bottom) production. Cytokine levels were measured at 24 h for human PBMCs incubated with 1 ng / mL LPS and serial dilutions (1000–0.2 nM) of steroid payload; <0.2 nM is plotted as no treatment control on the logarithmic x-axis. n = 2 donors; a representative donor is shown. Standard deviations plotted from technical duplicates. [Figure 54]INX-SM-32 inhibits IL-1β (top) and IL-6 (bottom) production. Cytokine levels were measured at 24 h for human PBMCs incubated with 1 ng / mL LPS and serial dilutions (500–1 nM) of steroid payload; <1 nM is the no treatment control plotted on the x-axis on a logarithmic scale; n = 2 donors. A representative donor is shown. Standard deviations plotted from technical duplicates. [Figure 55] INX-SM-10 shows robust inhibition of IL-1β (top) and IL-6 (bottom) production. INX-SM-33 demonstrated modest inhibition of cytokine production. Cytokine levels were measured at 24 hours for human PBMCs incubated with 1 ng / mL LPS and serial dilutions (1000 to 0.5 nM) of steroid payload; <0.5 nM is the no treatment control plotted on the x-axis on a logarithmic scale; n = 1 donor; standard deviations are plotted from technical duplicates. [Figure 56] INX-SM-2 and INX-SM-7 show inhibition of IL-1β. Cytokine levels were measured at 24 hours for human PBMCs incubated with 1 ng / mL LPS and serial dilutions (1000 to 0.16 nM) of steroid payload; <0.16 nM is plotted as no treatment control on the x-axis on a logarithmic scale, n=1, and standard deviations are plotted from technical duplicates. [Figure 57] This shows that halogenation of both C6 and C9, but not C9 alone, provides increased potency. Mean cytokine levels were measured at 24 hours for human PBMCs incubated with 1 ng / mL LPS and serial dilutions (1000 to 0.16 nM) of steroid payload; no treatment controls <0.16 nM are plotted on the x-axis on a logarithmic scale, n=1, and standard deviations are plotted from technical duplicates. [Figure 58]INX P-conjugated antibodies against other surface targets retain the anti-inflammatory effects of anti-VISTA conjugates. Mean cytokine levels were measured at 24 hours for human PBMCs incubated with 1 ng / mL LPS and serial dilutions of glucocorticoid conjugates (8,000 to 0.26 nM conjugate payload). n=1, mean of technical duplicates. [Figure 59] INX-SM-43 shows modest inhibition of huIL1-β. Mean cytokine levels were measured at 24 hours for human PBMCs incubated with 1 ng / mL LPS and serial dilutions of glucocorticoid payload (100–0.032 nM). n=1, mean of technical duplicates. [Figure 60] INX-SM-44 shows modest inhibition of huIL1-β. Mean cytokine levels were measured at 24 hours for human PBMCs incubated with 1 ng / mL LPS and serial dilutions of glucocorticoid payload (1000–0.32 nM). n=1, mean of technical duplicates. [Figure 61] INX-SM-25 and INX-SM-3 show robust inhibition of IL-1β production. INX-SM-45 and INX-SM-46 demonstrated more modest inhibition of cytokine production. Cytokine levels were measured at 24 hours for human PBMCs incubated with 1 ng / mL LPS and serial dilutions (1000 to 0.5 nM) of steroid payload; <0.5 nM is plotted as no treatment control on the logarithmic x-axis; n = 1 donor; mean of technical duplicates is plotted. [Figure 62]Dramatically increased potency of INX231V compared to INX231P and INX231J. Mean cytokine levels of A. huIL-1β and B. huIL-6 were measured at 24 hours for human PBMCs incubated with 1 ng / mL LPS and serial dilutions (1000–0.16 nM) of conjugated steroid payloads; no treatment controls <0.16 nM are plotted on the x-axis on a logarithmic scale, n=1, with standard deviations plotted from technical duplicates. Values ​​above the ULOQ (12,500 pg / mL for IL-1b and 150,000 pg / mL for IL-6) are plotted as insets. [Figure 63] INX231V has substantial potency, and INX231P has modest potency compared to INX231J. Mean cytokine levels of IL-1β were measured at 24 hours for human PBMCs incubated with 1 ng / mL LPS and serial dilutions (1000 to 0.16 nM) of conjugated steroid payloads; <0.16 nM no treatment controls are plotted on the x-axis on a logarithmic scale, n=1, and the mean of technical duplicates is plotted. [Figure 64] Improved potency of INX231S, INX234T, and INX234A3 compared to INX231J. Mean cytokine levels of IL-1β were measured at 24 hours for human PBMCs incubated with 1 ng / mL LPS and serial dilutions (1000–0.16 nM) of conjugated steroid payload, with <0.16 nM being no treatment control plotted on the x-axis on a logarithmic scale, n=1, and the mean of technical duplicates plotted. [Figure 65] INX201 may lead to improved early efficacy of the conjugate versus INX231. Mean cytokine levels of IL-1β were measured at 24 hours for human PBMCs incubated with 1 ng / mL LPS and serial dilutions (1000 to 0.16 nM) of conjugated steroid payload, with <0.16 nM being no treatment control plotted on the x-axis on a logarithmic scale, n=1, and the mean of technical duplicates plotted. [Figure 66]INX V analogs are more potent than INX231J. Mean cytokine levels of IL-1β were measured at 24 hours for human PBMCs incubated with 1 ng / mL LPS and serial dilutions (1000–0.16 nM) of conjugated steroid payloads; <0.16 nM no treatment controls were plotted on the x-axis on a logarithmic scale, n=1, and the mean of technical duplicates was plotted. [Figure 67] INX-SM-36, INX-SM-32 (top), and INX-SM-3, INX-SM-J2 (bottom) inhibit IL-1β. INX-SM-32 and INX-SM-36 inhibit IL-1β with potency similar to dexamethasone. INX-SM-3 and INX-SM-J2 have potency similar to budesonide. Cytokine levels were measured at 24 h for human PBMCs incubated with 1 ng / mL LPS and serial dilutions (1000–0.5 nM) of steroid payload; values ​​<0.5 nM are plotted on the logarithmic x-axis. n = 1 donor; mean of technical duplicates is plotted. [Figure 68] INX-SM-32, INX-J2, and INX-SM-3 induce similar inhibition of IL-1β, while INX-SM-37 weakly inhibits IL-1β. INX-SM-32, INX-J2, and INX-SM-3 inhibit IL-1β with similar potency. Cytokine levels were measured at 24 h for human PBMCs incubated with 1 ng / mL LPS and serial dilutions (1000–0.15 nM) of steroid payload; values ​​<0.5 nM were plotted on the logarithmic x-axis. n = 1 donor; mean of technical duplicates was plotted. [Figure 69] INX231V is substantially more potent than other INX231 / INX234 conjugates. Mean cytokine levels of IL-1β were measured at 24 hours for human PBMCs incubated with 1 ng / mL LPS and serial dilutions (1000 to 0.16 nM) of conjugated steroid payload; <0.16 nM no treatment controls are plotted on the x-axis on a logarithmic scale, n=1, and the mean of technical duplicates is plotted. [Figure 70] Phosphorylated and halogenated analogs of INX V are more potent than INX J. Mean cytokine levels of IL-1β were measured at 24 h for human PBMCs incubated with 1 ng / mL LPS and serial dilutions (1000–0.16 nM) of conjugated steroid payloads, with no treatment controls plotted on the x-axis on a logarithmic scale at <0.16 nM, n = 1, and the mean of technical duplicates plotted. [Figure 71] INX-SM-14, INX-SM-15, and INX-J2 have similar inhibition of IL-1β (top) and IL-6 (bottom). INX-SM-17 weakly inhibits IL-1β but not IL-6. INX-SM-14, INX-SM-15, and INX-J2 inhibit IL-1β and IL-6 with similar potency. Cytokine levels were measured at 24 h for human PBMCs incubated with 1 ng / mL LPS and serial dilutions (1000–0.15 nM) of steroid payload, with 0.01 nM being the no treatment control plotted on the x-axis on a logarithmic scale; n = 1 donor; mean of technical duplicates is plotted. [Figure 72] INX-SM-40 and INX-SM-34 weakly inhibit IL-1β (top) and IL-6 (bottom) compared to INX-J2. Cytokine levels were measured at 24 h for human PBMCs incubated with 1 ng / mL LPS and serial dilutions (1000–0.15 nM) of steroid payload, with 0.01 nM being the no treatment control plotted on the x-axis on a logarithmic scale, n = 1 donor, and the mean of technical duplicates plotted. [Figure 73] INX-SM-49 and INX-SM-47 weakly inhibit IL-1β (top) and IL-6 (bottom) compared to INX-J2. Cytokine levels (IL1-β and IL-6) were measured at 24 h for human PBMCs incubated with serial dilutions (1000–0.15 nM) of LPS and steroid payload at 1 ng / mL and 0.01 nM, respectively. No treatment control is plotted on the x-axis on a logarithmic scale; n = 1 donor; mean of technical duplicates is plotted. [Figure 74] INX231A9 and INX201V show improved potency compared to INX234J and INX201J in reducing IL-1β production. Cytokine levels were measured at 24 hours for human PBMCs incubated with 1 ng / mL LPS and serial dilutions of anti-VISTA conjugates for conjugate payload concentrations (1000 to 0.15 nM), with 0.1 nM being the no treatment control plotted on the x-axis on a logarithmic scale, n = 1 donor, and the mean of technical duplicates plotted. [Figure 75] INX V and INX A23 at equivalent or reduced DARs show improved potency in reducing IL-1β production compared to INX J. Cytokine levels were measured at 24 hours for human PBMCs incubated with 1 ng / mL LPS and serial dilutions of anti-VISTA conjugates for total ADC concentrations (20–0.003 μg / mL) and 0.001 μg / mL, with no treatment control plotted on the x-axis on a logarithmic scale, n = 1 donor, and the mean of technical duplicates plotted. [Figure 76] The INX V conjugate has improved potency in affecting IL-1β compared to the INX J conjugate, even at a reduced DAR. Cytokine levels were measured at 24 hours for human PBMCs incubated with 1 ng / mL LPS and serial dilutions of anti-VISTA conjugates for conjugate payload concentrations (20 to 0.003 μg / mL) and 0.001 μg / mL. No treatment control is plotted on the x-axis on a logarithmic scale, n = 1 donor, and the mean of technical duplicates is plotted. [Figure 77] 1 includes the results of an experiment comparing the PK properties of an exemplary antibody of the invention, INX200, versus human IgG1, as shown in the plasma concentrations of the antibodies at the annotated time points in hVISTA KI mice (SD; n=5 / group). [Figure 78] 1 includes the results of an experiment comparing the PK properties of 767-IgG1.3 versus human IgG1. Plasma concentrations of the antibodies at the annotated time points in hVISTA KI mice as indicated (SD; n=5 / group). [Figure 79] 1 includes the results of an experiment comparing the PK values ​​of other exemplary anti-VISTA antibodies according to the invention, namely, INX231, INX234, INX237, and INX240. As shown therein, plasma concentrations of antibodies (SD; n=5 / group) at annotated time points in hVISTA KI mice. The left graph shows the y-axis and x-axis in Log10, while for the right graph, only the y-axis is in Log10. [Figure 80] 1 includes the results of an experiment comparing PK values ​​of exemplary anti-VISTA antibodies according to the invention, namely, INX901, INX904, INX907, and INX908. Plasma concentrations of antibodies at annotated time points in hVISTA KI mice (SD; n=5 / group). [Figure 81] Figure 1 contains the results of an experiment comparing the PK values ​​of different ADCs according to the invention, namely INX201J, INX231J, INX234J, and INX240J. Plasma concentrations of antibodies at annotated time points in hVISTA KI mice (SD; n=4 / group). [Figure 82] 10 includes the results of an experiment assaying the effect of chronic treatment with the exemplary VISTA Ab ADC conjugate INX201J and dexamethasone on corticosterone levels. The figure shows the change in plasma corticosterone levels. (SEM, one-way ANOVA, n=8, except for the PBS control group in the right graph, which contains n=6.) [Figure 83] 1 shows the number of Ag-specific CD8 T cells from peripheral blood on day 6 after immunization in Experiment 1 of Example 12 (SEM, one-way ANOVA, n=5). [Figure 84] Figure 1 shows the number of Ag-specific CD8 T cells from peripheral blood on day 6 after immunization in Experiment 2 of Example 12. The graph on the left shows the PBS control group including all samples, and the graph on the right shows the PBS control group with one outlier removed (SEM, one-way ANOVA, n=5 excluding naive, one sample was excluded in the group with Dex at 0.2 mg / Kg as an immunization failure). [Figure 85]Figure 1 shows the number of Ag-specific CD8 T cells from peripheral blood on day 6 after immunization in Experiment 3 of Example 12. In this experiment, multiple samples had to be excluded due to technical issues during processing. PBS group n=3, Dex at 2 mg / kg n=2, Dex at 0.2 mg / kg n=3, INX201J D-1 n=5, INX201J D-7 n=2, INX231J D-7 n=3, INX234 J D-7 n=5, INX240 J D-7 n=4 (SEM, one-way ANOVA, D=day). [Figure 86] Figure 1 shows the number of Ag-specific CD8 T cells from peripheral blood on day 6 after immunization in Experiment 3 of Example 12. For technical reasons, two samples were excluded in the PBS, INX231P, and INX234P groups; for all other groups, n=5 (SEM, one-way ANOVA). [Figure 87] Changes in absolute cell counts in peripheral blood are shown for two experimental schedules: OVA challenge on days 14–18 and 21–25 (SEM, one-way ANOVA, n = 10 excluding naive, n = 5). [Figure 88] Changes in immunoglobulin production in peripheral blood in two experimental schedules: OVA challenge on days 14–18 (part 1) and days 21–25 (part 2) (SEM, one-way ANOVA, n = 10 excluding naive, n = 5). [Figure 89] Changes in immune infiltration in BAL in two experimental schedules: OVA challenge on days 14-18 (part 1) and days 21-25 (part 2); A) changes in bone marrow infiltration, B) changes in lymphocyte infiltration (SEM, one-way ANOVA, two samples censored for the control group, including 3 in both the Dex and INX201J groups, n = 10, n = 5 for the naive group). [Figure 90] Changes in cytokine levels in BAL in two experimental schedules are shown: OVA challenge on days 14–18 (part 1) and days 21–25 (part 2) (SEM, one-way ANOVA, two samples censored for the control group, n = 10 with 3 in both the Dex and INX201J groups, n = 5 for the naive group). [Figure 91] Lung disease scoring for Part 1 of the study is shown (SEM, one-way ANOVA, n=10 except for naive group n=5). [Figure 92] FKBP5 transcription activation after INX231J injection in spleen (left) and blood (right) cells is shown. INX231J efficacy and hIgG1siJ (gray) were measured 20 hours after a single intravenous injection at 5 mg / Kg (delivering a payload of 0.1 mg / Kg). Dex efficacy was measured 2 hours after a single intraperitoneal injection at 2 mg / Kg. FKBP5 transcription levels were measured by real-time PCR and presented as Log2 fold change versus the mean of the PBS control group. (n=4 mice / group, ordinary one-way ANOVA compared to the PBS-only group. [Figure 93] Figure 1 shows FKBP5 transcription activation after INX231P injection in C57Bl / 6 mice. INX231P effects were measured 20 hours after a single intravenous injection at 10 mg / Kg (delivering a payload of 0.2 mg / Kg). Dex effects were measured 2 hours after a single intraperitoneal injection at 2 mg / Kg. FKBP5 transcription levels were measured by real-time PCR and presented as Log2 fold change versus the mean of the PBS control group. (n=4 mice / group, ordinary one-way ANOVA compared to the PBS-only group). [Figure 94] Experimental results showing FKBP5 transcription activation after INX231P injection in C57Bl / 6 or hVISTA KI mice are included. INX231P effects were measured 20 hours after a single intravenous injection at 10 mg / kg (delivering a payload of 0.2 mg / kg). Dex effects were measured 2 hours after a single intraperitoneal injection at 2 mg / kg. FKBP5 transcription levels were measured by real-time PCR and presented as Log2 fold change versus the mean of the PBS control group. (n=4 mice / group, ordinary one-way ANOVA compared to the PBS-only group). [Figure 95]Experimental results are included showing that in vivo Dex treatment reduces the ex vivo monocyte inflammatory response to LPS. Mice were intraperitoneally injected with PBS or Dex at 2 mg / kg or 0.2 mg / kg. Two hours later, splenic monocytes were isolated, cultured, and stimulated with LPS at 0, 10, and 100 ng / ml. 24-hour supernatants were analyzed on a Luminex 32-plex (n = 5 mice / group, but samples 1, 2, 3, and 4, 5 were pooled into two samples). [Figure 96] Experimental results are included showing that in vivo treatment with INX231P affects the ex vivo monocyte inflammatory response to LPS. Mice were intraperitoneally injected with PBS or Dex at 2 mg / kg 2 hours, 2 days, or 6 days before cell isolation, and intravenously injected with INX231P and INX901 at 10 mg / kg 1, 3, and 7 days before cell isolation. After isolation, splenic monocytes were cultured and stimulated with LPS at 0 or 10 ng / ml (only 10 ng / ml is shown). 24-hour supernatants were analyzed by ELISA (n = 4 mice / group; one-way ANOVA comparing with the PBS-treated group was performed on day 1 (D1) samples only). [Figure 97] Experimental results are included showing that in vivo treatment with INX231P affects the ex vivo monocyte inflammatory response to LPS. Mice were injected intraperitoneally with PBS or Dex at 2 mg / kg 2 hours before cell isolation, and intravenously with INX231P and INX901 at 10 mg / kg 24 hours before cell isolation. Splenic monocytes were cultured and stimulated with LPS at 10 and 100 ng / ml. 24-hour supernatants were analyzed by ELISA (n = 4 mice / group, separate one-way ordinary ANOVA for each LPS dose compared to the PBS-treated group). [Figure 98] Figure 1 shows FKBP5 transcriptional activation in B cells or monocytes. Cells were treated with 20 nM free J payload, or equimolar amounts of payload conjugated to INX201 (INX201J) or isotype control (huIgG1si J). Transcript levels were analyzed in technical duplicates. [Figure 99]Figure 1 shows FKBP5 transcription activation in monocytes. Cells were treated with increasing amounts of INX201J (0-100 nM payload). 0 payload represents treatment with unconjugated INX201 antibody alone at the same amount of antibody as the 100 nM payload INX201J dose. Transcript levels were analyzed as technical duplicates. [Figure 100] Figure 1 shows FKBP induction in Tregs from two donors treated with 20 nM INX-SM-3 (free payload) or the molar payload equivalent of INX231P (conjugated payload). Samples were generated and analyzed singly. The purity of isolated Tregs was ≥ 75% as assessed by flow cytometry. [Figure 101] Figure 1 shows FKBP5 induction in Tregs from one donor treated with 20 nM payload equivalent of INX201J compared to 20 nM payload equivalent of huIgG1si J. Samples were analyzed as technical duplicates. The purity of isolated Tregs was ≥ 75% as assessed by flow cytometry. [Figure 102] Summarizes reported consensus RNA expression levels by different area cells for VISTA and other ADC targets (CD40, TNFα, CD74, CD163 (PRLR)) based on reported "transcripts per million" (TPM), where TPM < 10 represents minimal / no expression ("-"), TPM 10-100 represents low / moderate expression ("+"), and TPM > 100 represents high expression ("++"). [Figure 103] Quantification of antigen density of VISTA, CD74, CD163, and mTNFα on identified cell populations is summarized: A) monocytes express VISTA, CD74, and CD163; B) B cells express CD74; C) CD4+ T cells, D) CD4+ Tregs, and E) CD8+ T cells express VISTA (mean ± SD, n = 5 donors). [Figure 104]Summarizing the quantification of antigen density of VISTA, CD74, CD163, and mTNFα on identified cell populations in human blood: A) monocytes express VISTA, CD74, and CD163; B) B cells express CD74; C) neutrophils express VISTA; D) CD4+ T cells; E) CD4+ Tregs; F) CD8+ T cells express VISTA (mean ± SD, n=3). [Figure 105] Data are included to demonstrate that steroid-responsive genes in bone are significantly affected by free Dex, while the VISTA ADC (INX231P) has limited effects. In the figure, Fkpb5 is shown on the left, RANKL is shown in the center left, ddit4 is shown in the center right, and Fam107a is shown on the far right. In the experiment, INX231P effects were measured 20 hours after a single intraperitoneal injection at 10 mg / kg (delivering a payload of 0.2 mg / kg). Dex effects were measured 2 hours after a single intraperitoneal injection at 2 mg / kg. Gene transcription levels were measured by RNA sequencing and presented as normalized counts (n = 5 mice / group, ordinary one-way ANOVA compared to the PBS-only group). [Figure 106] These results compare the effects of VISTA ADC (INX234P) compared to vehicle control on steroid-responsive gene expression in peripheral blood cells of cynomolgus monkeys. In these experiments, INX234P effects were measured 24 hours after a single intravenous dose of 10 mg / Kg (delivering a payload of 0.2 mg / Kg). Gene transcription levels were measured by RNA sequencing and presented as normalized counts (n = 2 vehicle, n = 6 ADC / group, unpaired T-test vs. vehicle). [Figure 107]This study includes results from an experiment evaluating the effects of the VISTA ADC (INX234P) on specific non-target cells. The data show that INX234P had limited or no effect on FKBP5 in white fat, brain, and bone. Experiments measured INX234P effects 24 hours after a single intravenous dose at 10 mg / Kg (delivering a 0.2 mg / Kg payload) or on D8 (vehicle). Gene transcription levels were measured by RNA sequencing and presented as normalized counts. (n = 2 vehicle, n = 3 ADC / group for tissues; unpaired t-test vs. vehicle-INX234P was not significant.) [Figure 108] Results from experiments evaluating the effects of ADCs on steroid-responsive genes are included. Data indicate some residual Dex effect in white adipose tissue at 24 hours, with ADC gene expression similar to vehicle control. The effects of free Dex (2 mg / Kg) and INX234P (10 mg / Kg, delivering a 0.2 mg / Kg payload) were measured 24 hours or on day 8 (vehicle) after a single intravenous administration. Gene transcription levels were measured by RNA sequencing and presented as normalized counts. (n = 2 vehicle, n = 2 dexamethasone, n = 3 ADCs / group for tissue, unpaired T-test vs. vehicle). [Figure 109]These figures include experimental results showing that high accumulation of the active payload (INX-SM-3) at 24 hours in monkeys treated with INX234P correlates with VISTA-expressing tissues. Panel (A) shows the released payload (INX-SM-3) measured 24 hours after a single intravenous administration of either INX234P (10 mg / kg, delivering a payload of 0.2 mg / kg) or free dexamethasone (2 mg / kg). Panel (B) shows the cysteine-modified linker / payload (INXP-cys), and panel (C) shows dexamethasone. Panel (D) shows that the released payload (INX-SM-3) persisted in VISTA-expressing tissues in monkeys treated with INX234P at day 8. Accumulated compound levels were measured by LC-MS / MS and presented as ng of compound / g of tissue (n=3 ADC / group for INX234P, n=2 due to limited samples, n=2 Dex) excluding bone marrow on day 8 (Duod=duodenum). [Figure 110] We compared VISTA expression with other proteins on activated immune cells (monocytes), particularly those targeted by other steroid ADCs. In these experiments, human whole blood from healthy donors was activated with LPS (100 μL per well in a U-bottom 96-well plate, 1 μg / mL LPS, 2 hours at 37°C). Cell surface protein expression levels on activated immune (monocyte) cells were assessed by flow cytometry. Directly conjugated antibodies used for staining in these experiments included anti-VISTA clone GG8, CD163 clone GHI / 61, CD74 clone 332516, and mTNFα clone mAb11. As shown, the VISTA expression pattern was similar to that observed on non-activated cells, while other protein expression levels were low. Specifically, the mTNFα MFI was only slightly higher than the FMO (fluorescence minus 1) control. [Figure 111]

[0023] Figure 1 includes the results of an experiment evaluating the PK of an ADC according to the invention, i.e., INX234P, in cynomolgus monkeys. INX234P was administered intravenously at 15 mg / Kg. Animals were bled at the indicated time points, serum was isolated, and antibody levels were measured (n=4 cynomolgus monkeys, SEM). [Figure 112] Figure 1 shows the hematological changes induced by a single dose of INX234P. In these experiments, INX234P was administered intravenously at 15 mg / kg. Animals were bled at the indicated time points, blood smears were performed, and different cell populations were counted (n=4 cynomolgus monkeys, SEM) (WBC=white blood cells, NEUT=neutrophils, LYMPH=lymphocytes, MONO=monocytes, EOS=eosinophils, BASO=basophils, RBC=erythrocytes, Retic=reticulocytes). [Figure 113] This article contains the results of experiments to detect cortisol changes induced by a single dose of INX234P in individual animals. In these experiments, INX234P was administered intravenously at 15 mg / kg. Animals were bled at the indicated time points, serum was isolated, and cortisol levels were measured by ELISA (n=4 cynomolgus monkeys). [Figure 114] The results of an experiment to detect the PK of the linker payload (P-cys) and released payload (SM3) in PBL are included. INX234P was administered intravenously at 15 mg / Kg. Animals were bled at the indicated time points, and PBLs were isolated and analyzed by MS (n=4 cynomolgus monkeys, SEM). [Figure 115] The results of a PK assay that detected the PK of the linker payload (P-cys) and released payload (SM3) in serum are included. INX234P was administered intravenously at 15 mg / kg. Animals were bled at the indicated time points, and serum was isolated and analyzed by MS (n=4 cynomolgus monkeys, SEM). [Figure 116]The results of experiments are included that show that INX234P upregulates steroid-responsive genes in PBL.In these experiments, INX234P is intravenously administered at 15mg / Kg.Animal is bled at the indicated time points, PBL is isolated, and RNA is isolated, and gene transcription levels are measured by RNA sequencing, and are presented as fold change versus before bleed (n=4 cynomolgus monkeys). [Figure 117] Included is an experiment showing the effect of INX201J, INX231P, and INX231V on FKBP5 induction in human PBMCs for up to 4 hours, where FKBP5 induction as measured by RT PCR relative to GAPDH was detected in human PBMCs incubated with 1 μM of conjugated payload for 4 hours, n=1 donor. [Figure 118A] Included are trade names and chemical names and structures of exemplary glucocorticoid agonist compounds and glucocorticoid agonist-linker compounds of Formulas I, II, and III. [Figure 118B] Included are trade names and chemical names and structures of exemplary glucocorticoid agonist compounds and glucocorticoid agonist-linker compounds of Formulas I, II, and III. [Figure 118C] Included are trade names and chemical names and structures of exemplary glucocorticoid agonist compounds and glucocorticoid agonist-linker compounds of Formulas I, II, and III. [Figure 118D] Included are trade names and chemical names and structures of exemplary glucocorticoid agonist compounds and glucocorticoid agonist-linker compounds of Formulas I, II, and III. [Figure 118E] Included are trade names and chemical names and structures of exemplary glucocorticoid agonist compounds and glucocorticoid agonist-linker compounds of Formulas I, II, and III. [Figure 118F] Included are trade names and chemical names and structures of exemplary glucocorticoid agonist compounds and glucocorticoid agonist-linker compounds of Formulas I, II, and III. [Figure 118G]Included are trade names and chemical names and structures of exemplary glucocorticoid agonist compounds and glucocorticoid agonist-linker compounds of Formulas I, II, and III. [Figure 118H] Included are trade names and chemical names and structures of exemplary glucocorticoid agonist compounds and glucocorticoid agonist-linker compounds of Formulas I, II, and III. [Figure 118I] Included are trade names and chemical names and structures of exemplary glucocorticoid agonist compounds and glucocorticoid agonist-linker compounds of Formulas I, II, and III. [Figure 118J] Included are trade names and chemical names and structures of exemplary glucocorticoid agonist compounds and glucocorticoid agonist-linker compounds of Formulas I, II, and III. [Figure 118K] Included are trade names and chemical names and structures of exemplary glucocorticoid agonist compounds and glucocorticoid agonist-linker compounds of Formulas I, II, and III. [Figure 118L] Included are trade names and chemical names and structures of exemplary glucocorticoid agonist compounds and glucocorticoid agonist-linker compounds of Formulas I, II, and III. [Figure 118M] Included are trade names and chemical names and structures of exemplary glucocorticoid agonist compounds and glucocorticoid agonist-linker compounds of Formulas I, II, and III. [Figure 118N] Included are trade names and chemical names and structures of exemplary glucocorticoid agonist compounds and glucocorticoid agonist-linker compounds of Formulas I, II, and III. [Figure 118O] Included are trade names and chemical names and structures of exemplary glucocorticoid agonist compounds and glucocorticoid agonist-linker compounds of Formulas I, II, and III. [Figure 119]Results from GVHD experiments showing that INX234P treatment reduces human PBMC proliferation are included. In these experiments, peripheral blood was collected on day 21 and human CD45-positive cells were quantified by flow cytometry. Mice were dosed once a week from day 0 to day 34 (SEM, n=8 / group) (dosed at 10 mg / Kg, INX234P provided an INX P linker payload of 0.2 mg / kg). [Figure 120] Results from a GVHD experiment showing that INX234P treatment improves mouse survival. Mice were administered intraperitoneally at 10 mg / kg (or 0.2 mg / kg of INX234P linker payload) once weekly from day 0 to day 34. The top left graph shows the average weight change as a percentage of initial weight, the three bottom graphs show the % weight loss for individual mice, and the top right graph is a Kaplan-Meier survival curve. The upper (lower graph) or lower (upper graph) gray bars indicate the duration of treatment (SEM, n=8 / group). [Figure 121] A GVHD experiment was included demonstrating that INX234V / P treatment reduces human T cell proliferation. Peripheral blood was collected weekly starting on day 15 post-transplant, and human CD45+CD3+ positive cells were quantified by flow cytometry. Mice were dosed once a week starting on day 0 (SEM, n=8 / group) (dosed at 10 mg / Kg; INX234V and INX234P delivered 0.2 mg / kg of INX V or INX P linker payload, respectively). [Figure 122] Data obtained in a GVHD model are included, demonstrating that INX234V / P treatment improves mouse survival. Mice were administered intraperitoneally at 10 mg / kg (or 0.2 mg / kg of INX V or INX P linker payload) once a week starting on day 0. The top left graph shows the average weight change as a percentage of initial weight, the three bottom graphs show the % weight loss for individual mice, and the top right graph is a Kaplan-Meier survival curve. [Figure 123]Data obtained in a colitis model are included, demonstrating that INX234P treatment improves mouse survival. In the experiment, mice were administered both INX234P and INX234 intraperitoneally at 10 mg / kg (and, where applicable, 0.2 mg / kg INX234 linker payload) once weekly from day 0 to day 61. The upper left graph shows the average weight change as a percentage of initial weight, the three lower graphs show the % weight loss for individual mice, and the upper right graph is a Kaplan-Meier survival curve. The upper (lower graph) or lower (upper graph) gray bars indicate the treatment period (SEM, except for the INX234P group, which contained n=9; n=10 / group). [Figure 124] Data from a colitis model are included, demonstrating that high-dose dexamethasone treatment improves mouse survival. Mice were administered 2 (high) or 0.2 (low) mg / kg intraperitoneally once weekly from day 0 to day 61. The upper left graph shows the mean weight change as a percentage of initial weight, the three lower graphs show the % weight loss for individual mice, and the upper right graph is a Kaplan-Meier survival curve. The upper (lower graph) or lower (upper graph) gray bars indicate the duration of treatment (SEM, n=10 / group). [Figure 125] Data obtained in a colitis model are included, demonstrating that INX234V treatment improves mouse survival. In the experiment, mice were intraperitoneally administered 10 mg / kg of both INX234V and INX234 (and 0.2 mg / kg of INX V linker payload, where applicable) once weekly from days 21 to 80. The upper left graph shows the mean body weight change as a percentage of initial body weight, the three lower graphs show the % weight loss for individual mice, and the upper right graph is a Kaplan-Meier survival curve. The upper (lower graph) or lower (upper graph) gray bars indicate the duration of treatment (SEM, except for the INX234-treated group, where n = 5; n = 10 / group). [Figure 126]Data from a colitis model are included, demonstrating that low-dose dexamethasone treatment improves mouse survival. Mice were administered 2 (high) or 0.2 (low) mg / kg intraperitoneally once weekly from day 21 to day 80. The upper left graph shows the mean weight change as a percentage of initial weight, the three lower graphs show the % weight loss for individual mice, and the upper right graph is a Kaplan-Meier survival curve. The upper (lower graph) or lower (upper graph) gray bars indicate the duration of treatment (SEM, n=10 / group). [Figure 127] This study includes data obtained in a colitis model showing that INX234V treatment prevents T cell proliferation and activation. In the experiment, mice were intraperitoneally administered 10 mg / kg of INX234V or INX234 (and 0.2 mg / kg of V-linker payload, if applicable) and 2 (high) or 0.2 (low) mg / kg of Dex once weekly from days 21 to 80. The upper left graph shows naive T cell counts from blood for INX234V and INX234 vs. PBS on the left, and for Dex at high and low doses vs. PBS on the right. The lower left and right graphs show the frequency of CD45RB+ CD4+ T cells for the same groups, with the upper gray bar indicating the duration of treatment (SEM, except for the INX234-treated group, where n=5; n=10 / group). DETAILED DESCRIPTION OF THE INVENTION

[0140] Provided herein are novel glucocorticosteroids, glucocorticosteroid linkers, and antibody-drug conjugates (ADCs) comprising antibodies or antibody fragments that bind to antigens expressed on immune cells, typically human immune cells. In some embodiments, the ADCs comprise anti-human VISTA (V-region immunoglobulin-containing inhibitor of T-cell activation (1)) antibodies or anti-VISTA antigen-binding antibody fragments, e.g., those with short serum half-lives (approximately 24-27 hours or less in human VISTA knock-in rodents). In exemplary embodiments, the subject ADCs have rapid onset of action and are long-lasting because they are highly effectively internalized by immune cells, where they are cleaved to release a large amount of active steroid payload. The present invention also relates to the use of such ADCs and novel steroids for the treatment of autoimmune, allergic, and inflammatory conditions. The invention further relates to methods for using such ADCs to reduce the deleterious side effects and / or improve the efficacy of glucocorticoids by selectively delivering these anti-inflammatory agents to target immune cells, such as monocytes, neutrophils, T cells, Tregs, eosinophils, macrophages, dendritic cells, NK cells, and in particular myeloid cells, thereby reducing potential toxicity otherwise induced by steroid compounds on non-target cells.

[0141] Specifically, the present disclosure relates to an anti-VISTA antibody or antibody fragment, typically an antibody or antibody fragment that possesses a very short serum half-life under physiological conditions (≈pH 7.5), generally a serum half-life of 72 hours, 1-32 hours, 1-16 hours, 1-8 hours, 1-4 hours, or 1-2 hours ± 0.5 hours under physiological conditions (≈pH 7.5) in human VISTA knock-in rodents, and ≈3.5, 3, 2.5, or 2.3 days ± 0.5 days in primates (cynomolgus monkeys), and a glucocorticoid receptor antibody of any one of Formulas (I), (II), or (III) disclosed herein. and a glucocorticoid receptor agonist, optionally attached via a linker, e.g., a peptide or non-peptide linker that may be cleavable under certain conditions, e.g., an esterase-cleavable dipeptide linker, and optionally attached directly or indirectly to an antibody via a heterobifunctional or heterotrifunctional group, which, when administered to a subject in need thereof, delivers the glucocorticoid receptor agonist to a target immune cell, e.g., a monocyte, T cell, neutrophil, Treg, CD8 T cell, CD4 T cell, eosinophil, dendritic cell, NK cell, macrophage, or myeloid cell, resulting in functional internalization of the glucocorticoid receptor agonist therein, where it induces a desired inhibitory effect on inflammation without inducing, or with substantially reduced, adverse side effects, such as toxicity to non-target cells. Additionally provided are methods of making and using such ADCs, particularly for use in treating autoimmune, allergic, and inflammatory conditions, such as those previously identified.

[0142] More specifically, glucocorticoid agonist compounds having the following structure of formula (I): [ka] X is selected from phenyl, spiro[3.3]heptane, 3-6 membered heterocycle, cycloalkyl, spiroalkyl, spiroheterocycloalkyl, bicyclic alkyl, heterobicyclic alkyl, [1.1.1]bicyclopentane, bicyclo[2.2.2]octane, adamantane, and cubane, each of which can be independently substituted with 1-4 heteroatoms selected from F, Cl, Br, I, N, S, and O, and each of whose ring structures can include at least one skeletal heteroatom selected from N, S, and O, and optionally further substituted with 1-4 C1-3 alkyl or C1-3 perfluoroalkyl; Z is selected from phenyl, spiro[3.3]heptane, 3-6 membered heterocycle, cycloalkyl, spiroalkyl, spiroheterocycloalkyl, bicyclic alkyl, heterobicyclic alkyl, [1.1.1]bicyclopentane, bicyclo[2.2.2]octane, adamantane, and cubane, each of which can be independently substituted with 1-4 heteroatoms selected from F, Cl, Br, I, N, S, and O, and each of whose ring structures can include at least one skeletal heteroatom selected from N, S, and O, and optionally further substituted with 1-4 C1-3 alkyl or C1-3 perfluoroalkyl; Y is selected from CHR, O, S, and NR; E is selected from CH and O; G is selected from CH and N; Furthermore, when G is CH and X is phenyl, Z is not phenyl, the bond of G to X may optionally be selected from C alkyl and ethylene oxide, each of which may be independently substituted with 1-4 heteroatoms selected from N, S, and O, and optionally further substituted with 1-4 C alkyl; the bond of X to Z may occupy any available position on X and Z; The substituent NR1R2 may occupy any available position on Z; R1 is selected from H, linear or branched alkyl of 1 to 8 carbons, aryl, and heteroaryl groups, and the aryl and heteroaryl groups can be substituted with functional groups selected from alkyl, haloalkyl, halogen, biphenyl, nitro, nitrile, -OH, -O-alkyl, -NH2, alkylamino, dialkylamino, thiol, thioalkyl, guanidine, urea, carboxylic acid, alkoxyl, carboxamide, carboxylic acid ester, alkyl-C(O)O-, alkylamino-C(O)-, and dialkylaminoC(O)-; When R1 is H, R2 can be selected from H, linear or branched alkyl of 1 to 8 carbons, aryl, and heteroaryl groups, and the aryl and heteroaryl groups can be substituted with functional groups selected from alkyl, haloalkyl, halogen, biphenyl, nitro, nitrile, -OH, -O-alkyl, -NH2, alkylamino, dialkylamino, thiol, thioalkyl, guanidine, urea, carboxylic acid, alkoxyl, carboxamide, carboxylic acid ester, alkyl-C(O)O-, alkylamino-C(O)-, and dialkylaminoC(O)-; When R1 is H, a linear or branched alkyl of 1 to 8 carbons, or a heteroaryl, R2 is [(C=O)CH(W)NH]m-[C=O]-[V]kJ, C=O)OCH2-p-aminophenyl-NVJ, (C=O)OCH2-p-aminophenyl-N-[(C=O)CH(W)NH]m-[C=O]-[V]kJ, and [V]-(C=O)OCH-p-aminophenyl-N—[(C=O)CH(W)NH]-[C=O]-J; wherein m=1 to 6, k=0 to 1, and each occurrence of W may be independently selected from H, [(CH)R] where n=1 to 4, a branched alkyl chain terminating in R, and a linear or branched polyethylene oxide group containing 1 to 13 units; R3 is selected from H, methyl, ethyl, isopropyl, OH, O-alkyl, NH, NH-alkyl, N-dialkyl, SH, S-alkyl, guanidine, urea, carboxylic acid, carboxamide, carboxylic acid ester, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, wherein the aryl and heteroaryl substituents may be selected from alkyl, haloalkyl, halogen, biphenyl, nitro, nitrile, —OH, —O-alkyl, —NH, alkylamino, dialkylamino, thiol, thioalkyl, guanidine, urea, carboxylic acid, alkoxyl, carboxamide, carboxylic acid ester, alkyl-C(O)O—, alkylamino-C(O)—, and dialkylaminoC(O)—; V is an alkyl chain of 1 to 8 carbons, a linear or branched polyethylene oxide group containing 1 to 13 units, a linear or branched alkyl group containing 1 to 8 carbons, -O-alkyl, carboxylic acid, carboxamide, carboxylic acid ester, alkyl-C(O)O-, alkylamino-C(O)-, dialkylamino-C(O)-, a sequence of 1 to 3 amino acids, each amino acid independently selected from Glu, Gly, Asn, Asp, Gln, Leu, Lys, Ala, βAla, Phe, Val, and Cit. and a heteroaryl group, wherein the aryl and heteroaryl groups may be substituted with a functional group selected from alkyl, haloalkyl, halogen, biphenyl, nitro, nitrile, -OH, -NH2, alkylamino, dialkylamino, thiol, thioalkyl, guanidine, urea, carboxylic acid, alkoxyl, carboxamide, carboxylic acid ester, alkyl-C(O)O-, alkylamino-C(O)-, and dialkylaminoC(O)-; J is -NH2, N3, thio, cyclooctyne, -OH, -CO2H, transcyclooctene, alkynyl, propargyl, [ka] is a reactive group selected from wherein R32 is selected from Cl, Br, F, mesylate, and tosylate; R33 is selected from Cl, Br, I, F, OH, —ON-succinimidyl, —O-(4-nitrophenyl), —O-pentafluorophenyl, or —O-tetrafluorophenyl; and R34 is H, Me, tetrazine-H, and tetrazine-Me; R5 is -CH2OH, -CH2SH, -CH2Cl, -SCH2Cl, -SCH2F, -SCH2CF3, hydroxy, -OCH2CN, -OCH2Cl, -OCH2F, -OCH3, -OCH2CH3, -SCH2CN, and [ka] is selected from the group consisting of R6 and R7 are independently selected from hydrogen and C1-10 alkyl; Q is H, [ka] R8 can be C(O)R8, where R8 is a straight or branched alkyl of 1 to 8 carbons, or (C=O)NR4CHnNR4(C=O)OCH2-(V)nJ, where n=1-4 and R4=H, alkyl or branched alkyl, or P(O)OR4; A1 and A2 are independently selected from H and F; Unless otherwise specified, glucocorticoid agonist compounds are provided in which all possible stereoisomers are claimed.

[0143] Further, there is provided a glucocorticoid agonist compound having the structure of formula (II): [ka] During the ceremony, Y is selected from CH and O; E is selected from CH and O; G is selected from CH and N; L is selected from H and F; R5 is -CH2OH, -SCH2F, and [ka] is selected from A1 and A2 are independently selected from H and F; V is an alkyl chain of 1 to 8 carbons, a linear or branched polyethylene oxide group containing 1 to 13 units, a linear or branched alkyl group containing 1 to 8 carbons, -O-alkyl, carboxylic acid, carboxamide, carboxylic acid ester, alkyl-C(O)O-, alkylamino-C(O)-, dialkylamino-C(O)-, a sequence of 1 to 3 amino acids, each amino acid independently selected from Glu, Gly, Asn, Asp, Gln, Leu, Lys, Ala, βAla, Phe, Val, and Cit. and a heteroaryl group, wherein the aryl and heteroaryl groups may be substituted with a functional group selected from alkyl, haloalkyl, halogen, biphenyl, nitro, nitrile, -OH, -NH2, alkylamino, dialkylamino, thiol, thioalkyl, guanidine, urea, carboxylic acid, alkoxyl, carboxamide, carboxylic acid ester, alkyl-C(O)O-, alkylamino-C(O)-, and dialkylaminoC(O)-; J is -NH2, N3, thio, cyclooctyne, -OH, -CO2H, transcyclooctene, alkynyl, propargyl, [ka] is a reactive group selected from In the formula, R 32 is selected from Cl, Br, F, mesylate, and tosylate; R33 is selected from Cl, Br, I, F, OH, —ON-succinimidyl, —O-(4-nitrophenyl), —O-pentafluorophenyl, or —O-tetrafluorophenyl; and R34 is H, Me, tetrazine-H, and tetrazine-Me.

[0144] Also included are glucocorticoid agonist compounds having the structure of formula (III): [ka] During the ceremony, Y is selected from CH and O; E is selected from CH and O; G is selected from CH and N; L is selected from H and F; R5 is -CH2OH, -SCH2F, and [ka] is selected from A1 and A2 are independently selected from H and F; V is an alkyl chain of 1 to 8 carbons, a linear or branched polyethylene oxide group containing 1 to 13 units, a linear or branched alkyl group containing 1 to 8 carbons, -O-alkyl, carboxylic acid, carboxamide, carboxylic acid ester, alkyl-C(O)O-, alkylamino-C(O)-, dialkylamino-C(O)-, a sequence of 1 to 3 amino acids, each amino acid independently selected from Glu, Gly, Asn, Asp, Gln, Leu, Lys, Ala, βAla, Phe, Val, and Cit. and a heteroaryl group, wherein the aryl and heteroaryl groups may be substituted with a functional group selected from alkyl, haloalkyl, halogen, biphenyl, nitro, nitrile, -OH, -NH2, alkylamino, dialkylamino, thiol, thioalkyl, guanidine, urea, carboxylic acid, alkoxyl, carboxamide, carboxylic acid ester, alkyl-C(O)O-, alkylamino-C(O)-, and dialkylaminoC(O)-; J is -NH2, N3, thio, cyclooctyne, -OH, -CO2H, transcyclooctene, alkynyl, propargyl, [ka] is a reactive group selected from Also provided are glucocorticoid agonist compounds wherein R32 is selected from Cl, Br, F, mesylate, and tosylate; R33 is selected from Cl, Br, I, F, OH, -ON-succinimidyl, -O-(4-nitrophenyl), -O-pentafluorophenyl, or -O-tetrafluorophenyl; and R34 is H, Me, tetrazine-H, and tetrazine-Me.

[0145] Also provided are glucocorticoid agonist linker compounds comprising a glucocorticoid agonist having the structure of Formula (I), (II), or (III) attached to a cleavable or non-cleavable linker.

[0146] Further provided is an ADC comprising an antibody that binds to an immune cell antigen, e.g., VISTA, attached to a glucocorticoid agonist having the structure of Formula (I), (II), or (III), which in turn is attached to a cleavable or non-cleavable linker.

[0147] Additionally, compositions and medicaments are provided that include the glucocorticoid agonists, glucocorticoid agonist linkers, and ADCs containing them.

[0148] Further provided are therapeutic and prophylactic uses of such glucocorticoid agonists, glucocorticoid agonist linkers, and ADCs containing them, particularly for treating inflammatory, allergic, and autoimmune conditions.

[0149] Unless otherwise defined, and as commonly understood, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this invention belongs. Although methods and materials similar or equivalent to those described herein can be used in the practice of the present invention or in testing of the present invention, suitable methods and materials are described below. The materials, methods, and examples are illustrative only and are not intended to be limiting. The nomenclature utilized in connection with, and the laboratory procedures and techniques of, analytical chemistry, synthetic organic chemistry, and medicinal and pharmaceutical chemistry described herein are those well known and commonly used in the art. Standard techniques may be used for chemical synthesis, chemical analysis, pharmaceutical preparation, formulation, and delivery, and treatment of patients.

[0150] definition To facilitate understanding of this disclosure, several terms and phrases are defined below.

[0151] As used throughout this description and the claims that follow, the meanings of "a," "an," and "the" include plural references unless the context clearly dictates otherwise.

[0152] In this disclosure, the term "glucocorticosteroid" or "steroid" refers to a naturally occurring or synthetic steroid hormone that interacts with the glucocorticoid receptor. Non-limiting exemplary glucocorticosteroids include those described in WO2009 / 069032, US20180126000, and WO05 / 028495, among others, and preferably refer to the novel glucocorticoid agonists of Formula I, II, or III, as well as glucocorticoid agonist linkers and ADCs containing the glucocorticoid agonists disclosed herein. Non-limiting examples of known glucocorticosteroids include: [ka]

[0153] Other known glucocorticosteroids are described in WO 2009 / 069032. Specific examples of glucocorticosteroids include 16-alpha hydroxyprednisolone, dexamethasone, difluorasone, flumethasone, flunisolide, fluocinolone acetonide, fluticasone propionate, ciclesonide, methylprednisolone, prednisone, prednisolone, mometasone, triamcinolone acetonide, and novel glucocorticoid agonists of Formula I, II, or III, as well as glucocorticoid agonist linkers and ADCs comprising the same disclosed herein.

[0154] A "glucocorticosteroid derivative" is a compound derivatized by the addition or removal of one or more atoms or functional groups to facilitate attachment of the "glucocorticosteroid derivative" to another moiety, e.g., a linker and / or an antibody or antibody fragment. Generally, this addition or removal does not interfere with the activity of the "glucocorticosteroid derivative," i.e., its ability to induce anti-inflammatory activity upon internalization by immune cells. A "glucocorticosteroid derivative" specifically includes a "radical of a glucocorticosteroid" or a "glucocorticosteroid radical."

[0155] A "radical of a glucocorticosteroid" or "glucocorticosteroid radical" is produced by the removal of one or more atoms, i.e., hydrogen atoms, from the parent glucocorticosteroid to facilitate attachment of the parent glucocorticosteroid to another moiety, typically a linker. For example, a hydrogen atom may be removed from any suitable -NH group of the parent glucocorticosteroid, a hydrogen atom may be removed from any suitable -OH group of the parent glucocorticosteroid, a hydrogen atom may be removed from any suitable -SH group, a hydrogen atom may be removed from any suitable -N(H)- group, or a hydrogen atom may be removed from any suitable -CH, -CH, or -CH= group of the parent glucocorticosteroid.

[0156] As used herein, the terms "heterobifunctional group" or "heterotrifunctional group" refer to a chemical moiety ("Q" in the general formula of the ADCs disclosed herein) that can be used to optionally connect a linker and an anti-VISTA antibody or antibody fragment. Heterobi- and trifunctional groups are characterized by having different reactive groups on both ends of the chemical moiety. Non-limiting exemplary heterobifunctional groups are disclosed in U.S. Publication No. 20180126000, which is incorporated herein by reference, and are further exemplified in the Exemplary Embodiments section and Examples, e.g., the ADC conjugate disclosed in Example 3 of the present application, and the compounds in Figures 118A-O of the present application.

[0157] Heterobi- and trifunctional groups are well known in the art for specifically producing protein conjugates and antibody drug conjugates (ADCs). These moieties are characterized by having different reactive groups on either end of the chemical moiety. Non-limiting exemplary heterobifunctional groups include: [ka] Exemplary Heterotrifunctional Groups [ka]

[0158] As used herein, the terms "antibody" (antibody and antibody) are terms of art and may be used interchangeably herein to refer to a molecule that has an antigen-binding site that specifically binds to an antigen.

[0159] The term "antibody" refers to an immunoglobulin molecule that recognizes and specifically binds to a target, such as a protein, polypeptide, peptide, carbohydrate, polynucleotide, lipid, or a combination of the foregoing, through at least one antigen recognition site within the variable region of the immunoglobulin molecule. As used herein, the term "antibody" encompasses intact polyclonal antibodies, intact monoclonal antibodies, chimeric antibodies, humanized antibodies, human antibodies, fusion proteins containing an antibody, and any other modified immunoglobulin molecule, so long as the antibody exhibits the desired biological activity. Antibodies can be any of the five major classes of immunoglobulins: IgA, IgD, IgE, IgG, and IgM, or their subclasses (isotypes) (e.g., IgG1, IgG2, IgG3, IgG4, IgA1, and IgA2), based on the identity of their heavy chain constant domains, called α, δ, ε, γ, and μ, respectively. Different classes of immunoglobulins have different, well-known subunit structures and three-dimensional configurations. Antibodies can be naked or conjugated to other molecules, such as toxins or radioisotopes. As used herein, the term "antibody" includes bispecific and multispecific antibodies.

[0160] The term "antibody fragment" refers to a portion of an intact antibody. An "antigen-binding fragment" refers to a portion of an intact antibody that binds to an antigen. An antigen-binding fragment can include the antigen-determining variable region of the intact antibody. Examples of antibody fragments include, but are not limited to, Fab, Fab', F(ab')2, and Fv fragments, linear antibodies, and single-chain antibodies. An "antigen-binding fragment" can be a bispecific or multispecific antigen-binding fragment.

[0161] A "blocking" or "antagonist" antibody is an antibody that inhibits or reduces the biological activity of the antigen to which it binds, such as VISTA. In some embodiments, a blocking or antagonist antibody substantially or completely inhibits the biological activity of the antigen. The biological activity may be reduced by 10%, 20%, 30%, 50%, 70%, 80%, 90%, 95%, or even 100%.

[0162] An "enhancing" or "potentiating" antibody, or an "agonist" antibody, is an antibody that enhances or increases the biological activity of the antigen to which it binds, such as VISTA. In some embodiments, a blocking or antagonist antibody substantially or completely inhibits the biological activity of the antigen. Biological activity may be reduced by 10%, 20%, 30%, 50%, 70%, 80%, 90%, 95%, or even 100%.

[0163] The term "anti-VISTA antibody" or "antibody that binds to VISTA" refers to an antibody that specifically binds to VISTA, typically human VISTA, with sufficient affinity such that the antibody is useful for targeting VISTA-expressing immune cells. The extent of binding of an anti-VISTA antibody to unrelated, non-VISTA proteins may be less than about 10% of the binding of the antibody to VISTA, as measured, for example, by radioimmunoassay (RIA). In certain embodiments, an antibody that binds to VISTA has a dissociation constant (Kd) of ≦1 μM, ≦100 nM, ≦10 nM, ≦1 nM, or ≦0.1 nM. Exemplary anti-VISTA antibodies and fragments included in the subject ADCs will contain the same CDRs and / or the same variable heavy and light chain polypeptides as those of VSTB94 or VSTB49-116, i.e., have the sequences shown in Figures 8, 10, and 12, respectively.

[0164] A "monoclonal" antibody or antigen-binding fragment thereof refers to a homogeneous population of antibodies or antigen-binding fragments involved in highly specific recognition and binding of a single antigenic determinant or epitope. This is in contrast to polyclonal antibodies, which typically include different antibodies directed against different antigenic determinants. The term "monoclonal" antibody or antigen-binding fragment thereof encompasses both intact and full-length monoclonal antibodies, as well as antibody fragments (e.g., Fab, Fab', F(ab')2, Fv), single-chain (scFv) variants, fusion proteins containing an antibody portion, and any other modified immunoglobulin molecule containing an antigen recognition site. Furthermore, a "monoclonal" antibody or antigen-binding fragment thereof refers to such antibodies and antigen-binding fragments thereof produced in any number of ways, including, but not limited to, hybridoma, phage selection, recombinant expression, and transgenic animals.

[0165] The term "humanized" antibody or antigen-binding fragment thereof refers to forms of non-human (e.g., murine) antibodies or antigen-binding fragments that are specific immunoglobulin chains, chimeric immunoglobulins, or fragments thereof that contain minimal non-human (e.g., murine) sequence. Typically, humanized antibodies or antigen-binding fragments thereof are human immunoglobulins in which residues from the complementarity-determining regions (CDRs) are replaced ("CDR-grafted") by residues from the CDRs of a non-human species (e.g., mouse, rat, rabbit, hamster) having the desired specificity, affinity, and capacity (Jones et al., Nature 321:522-525 (1986); Riechmann et al., Nature 332:323-327 (1988); Verhoeyen et al., Science 239:1534-1536 (1988)). In some instances, Fv framework region (FR) residues of a human immunoglobulin are replaced with corresponding residues in an antibody or fragment from a non-human species having the desired specificity, affinity, and capacity. Humanized antibodies or antigen-binding fragments thereof can be further modified by substitution of additional residues within the Fv framework regions and / or the replaced non-human residues to refine and optimize the specificity, affinity, and / or capacity of the antibody or antigen-binding fragment. Generally, a humanized antibody or antigen-binding fragment thereof will comprise substantially all of at least one, and typically two or three, variable domains, including all or substantially all of the CDR regions corresponding to the non-human immunoglobulin, while all or substantially all of the FR regions are of human immunoglobulin consensus sequences. The humanized antibody or antigen-binding fragment thereof can also comprise at least a portion of an immunoglobulin constant region or domain (Fc), typically that of a human immunoglobulin. Examples of methods used to generate humanized antibodies are described in U.S. Pat. No. 5,225,539, Roguska et al., Proc. Natl. Acad. Sci., USA, 91(3):969-973 (1994), and Roguska et al., Protein Eng. 9(10):895-904 (1996).In some embodiments, a "humanized antibody" is a resurfaced antibody.

[0166] The "variable region" of an antibody refers to the variable region of the antibody light chain or the variable region of the antibody heavy chain, either alone or in combination. The heavy and light chain variable regions each consist of four framework regions (FRs) connected by three complementarity-determining regions (CDRs), also known as hypervariable regions. The CDRs in each chain are held in close proximity by the FRs and, together with the CDRs from the other chain, contribute to the formation of an antigen-binding site. There are at least two techniques for determining CDRs: (1) an approach based on interspecies sequence variability (i.e., Kabat et al., Sequences of Proteins of Immunological Interest, (5th ed., 1991, National Institutes of Health, Bethesda, Md.)), and (2) an approach based on crystallographic studies of antigen-antibody complexes (Al-lazikani et al. (1997) J. Molec. Biol. 273:927-948). In addition, a combination of these two approaches is sometimes used in the art to determine CDRs.

[0167] The Kabat numbering system is generally used when referring to residues within the variable domain (approximately residues 1-107 of the light chain and residues 1-113 of the heavy chain). (See, e.g., Kabat et al., Sequences of Immunological Interest. 5th Ed. Public Health Service, National Institutes of Health, Bethesda, Md. (1991)). Unless explicitly stated otherwise, the numbering system used herein is the Kabat numbering system.

[0168] Kabat-like amino acid position numbering refers to the numbering system used for the heavy or light chain variable domains of a collection of antibodies in Kabat et al., Sequences of Proteins of Immunological Interest, 5th Ed. Public Health Service, National Institutes of Health, Bethesda, Md. (1991). Using this numbering system, the actual linear amino acid sequence can contain fewer or additional amino acids corresponding to shortening of, or insertion into, the FRs or CDRs of the variable domain. For example, a heavy chain variable domain can contain a single amino acid insertion after residue 52 of H2 (residue 52a according to Kabat) and inserted residues after heavy chain FR residue 82 (e.g., residues 82a, 82b, and 82c according to Kabat). The Kabat numbering of residues can be determined for a given antibody by alignment of the region of homology of the antibody's sequence with the "standard" Kabat-numbered sequence. Chothia instead refers to the location of the structural loops (Chothia and Lesk J. Mol. Biol. 196:901-917 (1987)). The termination of the Chothia CDR-H1 loop when numbered using the Kabat numbering convention varies between H32 and H34 depending on the length of the loop (this is because the Kabat numbering scheme places the insertion at H35A and H35B; if neither 35A nor 35B is present, the loop terminates at 32; if only 35A is present, the loop terminates at 33; and if both 35A and 35B are present, the loop terminates at 34). The AbM hypervariable regions represent a compromise between the Kabat CDRs and the Chothia structural loops and are used by Oxford Molecular's AbM antibody modeling software.

[0169] In certain embodiments, the CDRs of an antibody or antigen-binding fragment thereof may be determined according to the Chothia numbering scheme, which refers to the position of the immunoglobulin structural loops (see, e.g., Chothia C & Lesk AM, (1987), J Mol Biol 196:901-917; Al-Lazikani B et al., (1997) J Mol Biol 273:927-948; Chothia C et al., (1992) J Mol Biol 227:799-817; Tramontano A et al., (1990) J Mol Biol 215(1):175-82; and U.S. Patent No. 7,709,226). Typically, using the Kabat numbering convention, the Chothia CDR-H1 loop is located at heavy chain amino acids 26-32, 33, or 34, the Chothia CDR-H2 loop is located at heavy chain amino acids 52-56, and the Chothia CDR-H3 loop is located at heavy chain amino acids 95-102, while the Chothia CDR-L1 loop is located at light chain amino acids 24-34, the Chothia CDR-L2 loop is located at light chain amino acids 50-56, and the Chothia CDR-L3 loop is located at light chain amino acids 89-97. The terminus of the Chothia CDR-H1 loop when numbered using the Kabat numbering convention varies between H32 and H34 depending on the length of the loop (this is because the Kabat numbering scheme places the insertion at H35A and H35B; if neither 35A nor 35B is present, the loop ends at 32; if only 35A is present, the loop ends at 33; and if both 35A and 35B are present, the loop ends at 34).

[0170] In certain embodiments, the CDRs of an antibody or antigen-binding fragment thereof can be determined by the IMGT numbering system, as described in Lefranc MP, (1999) The Immunologist 7:132-136, and Lefranc MP et al., (1999) Nucleic Acids Res 27:209-212. According to the IMGT numbering scheme, VH-CDR1 is located at positions 26-35, VH-CDR2 is located at positions 51-57, VH-CDR3 is located at positions 93-102, VL-CDR1 is located at positions 27-32, VL-CDR2 is located at positions 50-52, and VL-CDR3 is located at positions 89-97.

[0171] In certain embodiments, the CDRs of an antibody or antigen-binding fragment thereof can be determined according to MacCallum RM et al., (1996) J Mol Biol 262:732-745. See also, for example, Martin A. "Protein Sequence and Structure Analysis of Antibody Variable Domains," in Antibody Engineering, Kontermann and Dubel, eds., Chapter 31, pp. 422-439, Springer-Verlag, Berlin (2001).

[0172] In certain embodiments, the CDRs of an antibody or antigen-binding fragment thereof represent a compromise between the Kabat CDRs and the Chothia structural loops and may be determined according to the AbM numbering scheme, which refers to the AbM hypervariable regions used by Oxford Molecular's AbM antibody modeling software (Oxford Molecular Group, Inc.).

[0173] A "constant region" of an antibody refers to the constant region of the antibody light chain or the constant region of the antibody heavy chain, either alone or in combination.

[0174] The term "human" antibody refers to an antibody produced by a human or an antibody having an amino acid sequence corresponding to an antibody produced by a human, made using any technique known in the art. This definition of human antibody includes intact or full-length antibodies, fragments thereof, and / or antibodies comprising at least one human heavy and / or light chain polypeptide, such as an antibody comprising a murine light chain and a human heavy chain polypeptide.

[0175] The term "chimeric" antibody refers to an antibody in which the amino acid sequences of the immunoglobulin molecules are derived from two or more species. Typically, the variable regions of both the light and heavy chains correspond to the variable regions of antibodies derived from one species of mammal (e.g., mouse, rat, rabbit, etc.) having the desired specificity, affinity, and capacity, while the constant regions are homologous to sequences in antibodies derived from that species to avoid eliciting an immune response in another species (usually human).

[0176] The terms "epitope" and "antigenic determinant" are used interchangeably herein and refer to that portion of an antigen that is capable of being recognized by and specifically binding to a particular antibody. When the antigen is a polypeptide, epitopes can be formed from both contiguous and non-contiguous amino acids juxtaposed by tertiary folding of the protein. Epitopes formed from contiguous amino acids are typically retained upon protein denaturation, while epitopes formed by tertiary folding are typically lost upon protein denaturation. An epitope typically comprises at least three, more usually at least five or 8-10 amino acids in a unique spatial conformation. Preferred epitopes on VISTA to which exemplary anti-VISTA antibodies may bind are identified in Figure 10.

[0177] "Binding affinity" generally refers to the strength of the sum of noncovalent interactions between a single binding site of a molecule (e.g., an antibody) and its binding partner (e.g., an antigen). Unless otherwise indicated, as used herein, "binding affinity" refers to the intrinsic binding affinity, which reflects a 1:1 interaction between members of a binding pair (e.g., an antibody and an antigen). The affinity of molecule X for its partner Y can generally be expressed by the dissociation constant (Kd). Affinity can be measured by common methods known in the art, including those described herein. Low-affinity antibodies generally bind antigens slowly and tend to dissociate easily, while high-affinity antibodies generally bind antigens faster and tend to remain bound longer. Various methods for measuring binding affinity are known in the art, any of which can be used for purposes of the present disclosure. Such methods include surface plasmon resonance (BIAcore), ELISA, Kinexa Biosensor, scintillation proximity assay, ORIGEN immunoassay (IGEN), fluorescence quenching, fluorescence transfer, and / or yeast display. Binding affinity can also be screened using a suitable bioassay. In this application, the Kd of the exemplary anti-VISTA antibody contained in the exemplary ADC was determined by surface plasmon resonance (SPR) on a ProteOn instrument.

[0178] As used herein, "or better" to refer to binding affinity refers to stronger binding between a molecule and its binding partner. As used herein, "or better" refers to stronger binding, represented by a smaller Kd value. For example, an antibody having an affinity for an antigen of "0.6 nM or greater," wherein the affinity of the antibody for the antigen is <0.6 nM, i.e., 0.59 nM, 0.58 nM, 0.57 nM, etc., or any value less than 0.6 nM.

[0179] "Specifically bind" generally means that an antibody binds to an epitope via its antigen-binding domain, and the binding involves a degree of complementarity between the antigen-binding domain and the epitope. According to this definition, an antibody is said to "specifically bind" to an epitope when it binds to that epitope via its antigen-binding domain more readily than it binds to a random, unrelated epitope. The term "specificity" is used herein to define the relative affinity with which a particular antibody binds to a particular epitope. For example, antibody "A" may be considered to have higher specificity for a given epitope than antibody "B," or antibody "A" may be said to bind to epitope "C" with higher specificity than it has for related epitope "D."

[0180] "Preferentially binds" means that an antibody specifically binds to an epitope more readily than it would bind to a related, similar, homologous, or analogous epitope. Thus, an antibody that "preferentially binds" to a given epitope will more likely bind to that epitope than to a related epitope, even if such an antibody may cross-react with the related epitope.

[0181] An antibody is said to "competitively inhibit" the binding of a reference antibody to a given epitope if the antibody preferentially binds to that epitope or an overlapping epitope to such an extent that it blocks the binding of the reference antibody to that epitope to some extent. Competitive inhibition can be determined by any method known in the art, for example, by competitive ELISA assay. An antibody can be said to competitively inhibit the binding of the reference antibody to a given epitope by at least 90%, at least 80%, at least 70%, at least 60%, or at least 50%.

[0182] "Isotype" herein refers to the antibody class (e.g., IgM, IgG1, IgG3, IgG3, or IgG4) that is encoded by heavy chain constant region genes.

[0183] "K-assoc" or "Ka" as used herein broadly refers to the association rate of a particular antibody-antigen interaction, while the terms "Kdiss" or "Kd" as used herein refer to the dissociation rate of a particular antibody-antigen interaction.

[0184] The term "KD" as used herein refers to the dissociation constant, which is obtained from the ratio of Kd to K (i.e., Kd / K) and expressed as a molar concentration (M). KD values ​​for antibodies can be determined using methods well established in the art, such as plasmon resonance (BIAcore®), ELISA, and KINEXA. A preferred method for determining the KD of an antibody is by using surface plasmon resonance, preferably by using a biosensor system such as a BIAcore® system, or by ELISA. Typically, these methods are performed at 25°C or 37°C. Antibodies for therapeutic use will generally possess a KD as determined by surface plasmon resonance of 50 nM or less, or more typically, 1 nM or less, at 25°C or 37°C.

[0185] The term "Kd" herein refers to the equilibrium dissociation constant, which is the calculated ratio of Koff / Kon between an antibody and its antigen. The association constant (Kon) is used to characterize how quickly an antibody binds to its target. Herein, antibody Kd was determined by surface plasmon resonance (SPR) using a Proteon instrument.

[0186] The term "PK" as used herein refers to the in vivo half-life or duration (in hours) during which half of the amount of an antibody or antibody fragment or antibody drug conjugate (ADC), preferably an anti-VISTA or antibody fragment according to the present invention (i.e., one comprising an anti-VISTA antibody or antibody fragment that binds to VISTA-expressing cells at physiological pH), and an anti-inflammatory agent (AI), which is a small molecule that requires cellular internalization for efficacy (anti-inflammatory activity), typically a steroid, more typically a glucocorticosteroid agonist of Formula I, II or III, remains in the peripheral circulation in serum. PK can be determined in vivo in a subject administered the antibody or antibody fragment or ADC, e.g., a human VISTA knock-in rodent, or in a primate (e.g., a human or cynomolgus monkey). As described below, anti-VISTA antibodies included in ADCs according to the invention will typically have short PK, i.e., generally about 2.3±0.7 days in cynomolgus monkeys, and typically at most ≈2.5 days, more typically only one day, a few hours or less, in human VISTA knock-in rodents.

[0187] The phrase "PD" herein refers to the duration (hours) over which an antibody or antibody drug conjugate (ADC) according to the invention, e.g., one comprising an anti-VISTA antibody or antibody fragment that binds to VISTA-expressing cells at physiological pH, and an anti-inflammatory agent (AI), a small molecule that requires cellular internalization for efficacy (anti-inflammatory activity), typically a steroid, more typically a glucocorticosteroid agonist of Formula I, II, or III, administered dose of the AI ​​elicits efficacy (anti-inflammatory activity) upon internalization into target cells. The PD of a steroid, e.g., a glucocorticosteroid agonist of Formula I, II, or III, or an ADC containing a glucocorticoid agonist linker disclosed herein and the same linker, can be determined by different assays. For example, the PD of a VISTA ADC according to the invention can be determined in vitro using VISTA-expressing immune cells contacted with the ADC, or can be determined in vivo in a subject, e.g., a rodent or primate (e.g., a human or cynomolgus monkey), that has been administered an ADC dose. In addition, because exemplary anti-VISTA ADCs bind to different immune cells (e.g., T cells, Tregs, monocytes, macrophages, neutrophils), and because these ADCs internalize different types of immune cells based on the relative expression of the antigen bound by them, e.g., VISTA expression, on those immune cells, and because turnover rates of such immune cells vary, PD values ​​will vary when determined in vitro using different types of immune cells, e.g., VISTA-expressing immune cells. Generally, as used herein, in the case of anti-VISTA ADCs, PD is expressed based on the duration of anti-inflammatory activity elicited by macrophages as these cells reside in the circulation, and it has (surprisingly) been demonstrated that VISTA antibodies, including ADCs according to the invention, elicit long-lasting anti-inflammatory activity in macrophages, for example, for several weeks or even a month after ADC administration.However, if the ADC targets immune cells different from VISTA, e.g., B cells or NK cells, PD would potentially be determined by detecting inflammatory activity within these cells, as internalization of the glucocorticoid agonist occurs within these cells.

[0188] The phrase "PD / PK ratio" herein refers to the ratio of PD and PK values ​​of an ADC according to the invention, determined in vitro or in vivo, e.g., in the case of an anti-VISTA ADC in a human VISTA knock-in rodent or primate (e.g., human or cynomolgus monkey), in immune cells of a particular species, or in an animal model. [As shown below, the PD / PK ratios of anti-VISTA ADCs according to the invention are surprisingly high, i.e., values ​​as high as 14:1 or 28:1 have been demonstrated in VISTA knock-in rodents and cynomolgus monkeys.] Furthermore, because the expression of VISTA by different immune cells in rodents and humans and primates is very similar, and because drug metabolism generally occurs much more rapidly in rodents than in humans and non-human primates, similar or higher PD / PK ratios are expected to be obtained in humans and other non-human primates. Although the applicant does not wish to be bound by this theory, it is believed that in the case of VISTA antibody-containing ADCs according to the present invention, the subject ADCs internalize specific types of VISTA-expressing cells in very large quantities due to the high density of surface VISTA expression on these immune cells, apparently creating a "depot effect," i.e., the depot of internalized ADC is metabolized very slowly, thereby providing a surprisingly prolonged release of a therapeutically effective (anti-inflammatory) amount of an anti-inflammatory agent (e.g., a steroid such as a glucocorticosteroid agonist of Formula I, II, or III, or a glucocorticosteroid agonist linker, or an ADC containing the same).

[0189] "Onset of efficacy" refers to the time at which the effectiveness of a therapeutic agent, e.g., a steroid or ADC conjugate, begins in vivo. In the present invention, this can be detected in a subject administered a glucocorticosteroid agonist of Formula I, II, or III, or a glucocorticosteroid agonist linker, or an ADC conjugate according to the present invention, using known in vivo assays that detect the anti-inflammatory effects of steroids. As disclosed below, anti-VISTA ADCs according to the present invention have been shown to have a rapid onset of efficacy, i.e., approximately 2 hours, in human VISTA knock-in rodents.

[0190] The phrases "substantially similar" or "substantially the same," as used herein, refer to a sufficiently high degree of similarity between two numerical values ​​such that one of ordinary skill in the art would consider the difference between the two values ​​(typically one value associated with an antibody of the present disclosure and the other value associated with a reference / comparator antibody) to have little or no biological and / or statistical significance within the context of the biological property measured by the values ​​(e.g., Kd values). The difference between the two values ​​can be less than about 50%, less than about 40%, less than about 30%, less than about 20%, or less than about 10% as a function of the value of the reference / comparator antibody.

[0191] An "isolated" polypeptide, antibody, polynucleotide, vector, cell, or composition is a polypeptide, antibody, polynucleotide, vector, cell, or composition that is in a form not found in nature. Isolated polypeptides, antibodies, polynucleotides, vectors, cells, or compositions include those that have been purified to the extent that they are no longer in the form in which they are found in nature. In some embodiments, an isolated antibody, polynucleotide, vector, cell, or composition is substantially pure.

[0192] As used herein, "substantially pure" refers to a material that is at least 50% pure (i.e., free from contaminants), at least 90% pure, at least 95% pure, at least 98% pure, or at least 99% pure.

[0193] The term "immunoconjugate," "conjugate," "antibody drug conjugate," or "ADC" as used herein refers to a compound that is attached to an anti-VISTA antibody or fragment thereof (or derivative thereof) and an anti-inflammatory agent, such as a glucocorticosteroid agonist, and generally has the following general formula: (AI-LQ): n- "A" refers to an intervening linker, which may be represented by A, where AI = anti-inflammatory agent, generally a small molecule glucocorticoid receptor agonist, e.g., a glucocorticosteroid agonist compound according to Formula 1, II, or III disclosed herein; L = linker; Q = heterobifunctional, heterotrifunctional, or absent; A = an anti-VISTA antibody or VISTA-binding fragment thereof that preferentially binds to human VISTA at physiological pH and generally possesses a short pK as described above; and n is an integer greater than 1, optionally 1 to 10. The immune complex may also be defined in reverse order by the following general formula: A-(QL-AI) n .

[0194] In the present disclosure, the term "linker" refers to any chemical moiety capable of attaching an antibody or antibody fragment (e.g., an antigen-binding fragment), or functional equivalent thereof, to an anti-inflammatory agent, generally a glucocorticosteroid receptor agonist, e.g., a glucocorticosteroid agonist of Formula I, II, or III. The linker may be susceptible to cleavage (a "cleavable linker"), thereby facilitating release of the anti-inflammatory agent, such as a glucocorticosteroid. For example, such a cleavable linker may be susceptible to acid-induced cleavage, photo-induced cleavage, peptidase-induced cleavage, esterase-induced cleavage, and disulfide bond cleavage under conditions under which the glucocorticosteroid and / or antibody remain active before or after internalization into immune cells such as neutrophils, monocytes, macrophages, eosinophils, T cells, dendritic cells, Tregs, NK cells, B cells, mast cells, macrophages, or myeloid cells, among other immune cell types. Alternatively, the linker may be substantially resistant to cleavage (a "non-cleavable linker").

[0195] Non-cleavable linkers include any chemical moiety that can attach an anti-inflammatory agent, such as a glucocorticosteroid agonist of Formula I, II, or III, to an antibody in a stable covalent manner and does not fall into the categories listed above for cleavable linkers. Thus, non-cleavable linkers are substantially resistant to acid-induced cleavage, photo-induced cleavage, peptidase-induced cleavage, esterase-induced cleavage, and disulfide bond cleavage. Furthermore, non-cleavable refers to the ability of the linker or a chemical bond adjacent to the linker to withstand cleavage induced by acid, photolabile cleaving agents, peptidases, elastases, or chemical or physiological compounds that cleave disulfide bonds under conditions such that the glucocorticosteroid and / or antibody do not lose their activity before or after internalization into immune cells such as monocytes or myeloid cells.

[0196] Some cleavable linkers are cleaved by peptidases ("peptidase-cleavable linkers"). Only certain peptides are readily cleaved inside or outside cells. See, for example, Trout et al., 79 Proc. Natl. Acad. Sci. USA, 626-629 (1982) and Umemoto et al., 43 Int. J. Cancer, 677-684 (1989). Furthermore, peptides are composed of α-amino acid units and peptide bonds, which are chemically amide bonds between the carboxylate group of one amino acid and the amino group of a second amino acid. Other amide bonds, such as the bond between the carboxylate group and the α-amino acid group of lysine, are understood to be non-peptide bonds and are considered non-cleavable.

[0197] Some linkers are cleaved by esterases ("esterase-cleavable linkers"). Only certain esters can be cleaved by esterases present inside or outside the cell. Esters are formed by the condensation of a carboxylic acid and an alcohol. Simple esters are esters produced with simple alcohols, such as aliphatic alcohols and small cyclic and small aromatic alcohols.

[0198] In some embodiments, the cleavable linker component may comprise a peptide comprising 1 to 10 amino acid residues. In these embodiments, the peptide allows for cleavage of the linker by a protease, thereby promoting the release of an anti-inflammatory agent, e.g., a glucocorticosteroid, upon exposure to an intracellular protease, such as a lysosomal enzyme (Doronina et al. (2003) Nat. Biotechnol. 21:778-784). Exemplary peptides include, but are not limited to, dipeptides, tripeptides, tetrapeptides, and pentapeptides. Exemplary dipeptides include, but are not limited to, alanine-alanine (ala-ala), valine-citrulline (vc or val-cit), alanine-phenylalanine (af or ala-phe), phenylalanine-lysine (fk or phe-lys), phenylalanine-homolysine (phe-homolys), and N-methyl-valine-citrulline (Me-val-cit). Exemplary tripeptides include, but are not limited to, glycine-valine-citrulline (gly-val-cit) and glycine-glycine-glycine (gly-gly-gly), as well as the specific linkers identified in the "Exemplary Embodiments" section and embodied in Example 3 of the present application.

[0199] Peptides can contain naturally occurring and / or unnatural amino acid residues. The term "naturally occurring amino acid" refers to Ala, Asp, Cys, Glu, Phe, Gly, His, He, Lys, Leu, Met, Asn, Pro, Gin, Arg, Ser, Thr, Val, Trp, and Tyr. "Unnatural amino acids" (i.e., amino acids not occurring in nature) include, by non-limiting example, homoserine, homoarginine, citrulline, phenylglycine, taurine, iodotyrosine, selenocysteine, norleucine ("Nle"), norvaline ("Nva"), beta-alanine, L- or D-naphthalenine, ornithine ("Orn"), and the like. Peptides can be designed and optimized for enzymatic cleavage by specific enzymes, such as tumor-associated proteases, cathepsins B, C, and D, or plasmin proteases.

[0200] Amino acids also include D-forms of natural and unnatural amino acids. "D-" designates an amino acid having a "D" (dextrorotatory) configuration, as opposed to the configuration in naturally occurring ("L-") amino acids. Natural and unnatural amino acids can be purchased commercially (Sigma Chemical Co., Advanced Chemtech) or synthesized using methods known in the art.

[0201] The term "drug-antibody ratio" or "DAR" refers to the number of anti-inflammatory agents or functional derivatives (i.e., radicals derived from small molecule glucocorticoid receptor agonists, e.g., glucocorticosteroids of Formula I, II, or III). Thus, the general formula (AI-LQ) n In immunoconjugates with -A or vice versa, the DAR is defined by the variable "n." Typically, in the subject ADCs, "n" ranges from 1 to 12.

[0202] Formula for individual immune complexes (AI-LQ) nWhen referring to a compound having -A, DAR refers to the number of inflammatory agents or functional derivatives (e.g., small molecule glucocorticoid receptor agonists, e.g., glucocorticosteroids such as dexamethasone or budesonide, or radicals derived from novel glucocorticosteroids of Formula I, II, or III, that are attached to A (e.g., n is optionally an integer or fraction from 1 to 12).

[0203] Formula for multiple immune complexes (AI-LQ) n When referring to a compound having -A, DAR refers to the average number of radicals (e.g., n is optionally an integer or fractional number from 1 to 12) derived from an anti-inflammatory agent or functional derivative (e.g., a small molecule glucocorticoid receptor agonist, e.g., a glucocorticosteroid, such as a novel steroid of Formula I, II, or III), that are attached to A by a linker. Thus, an example includes a first immunoconjugate having three AIs per A and a second immunoconjugate having four AIs per A, such as a compound of the formula (AI-LQ) n A compound with -A would have a DAR (i.e., "n") of 3.5.

[0204] The term "subject" refers to any animal (e.g., mammal), including but not limited to humans, non-human primates, rodents, and the like, who will be the recipient of a particular treatment. Typically, the terms "subject" and "patient" are used interchangeably herein in reference to a human subject.

[0205] The term "pharmaceutical formulation" refers to a preparation that is in a form that allows the biological activity of the active ingredient to be effective and that does not contain additional ingredients that are unacceptably toxic to the subject to which the formulation is administered. The formulation may be sterile.

[0206] An "effective amount" of an ADC or glucocorticoid receptor agonist disclosed herein is an amount sufficient to carry out a specifically stated purpose. An "effective amount" can be determined with respect to the stated purpose.

[0207] The term "therapeutically effective amount" refers to an amount of an immunoconjugate or glucocorticoid receptor agonist effective to "treat" a disease or disorder in a subject or mammal. A "prophylactically effective amount" refers to an amount effective to achieve a desired prophylactic result.

[0208] Terms such as "treating" or "treatment" or "treat" or "alleviating" refer to therapeutic measures that cure, slow, or relieve the symptoms of a diagnosed pathological condition or disorder, and / or halt the progression of the condition or disorder. Thus, those in need of treatment include those already diagnosed with a disorder or suspected of having a diagnosis. Prophylactic or preventative measures refer to measures that prevent and / or slow the onset of the targeted pathological condition or disorder. Thus, those in need of prophylactic or preventative measures include those prone to having a disorder and those in whom a disorder is to be prevented.

[0209] "Polynucleotide" or "nucleic acid," as used interchangeably herein, refer to a polymer of nucleotides of any length, and include DNA and RNA. The nucleotides can be deoxyribonucleotides, ribonucleotides, modified nucleotides or bases, and / or their analogs, or any substrate that can be incorporated into a polymer by DNA or RNA polymerase. A polynucleotide can comprise modified nucleotides, such as methylated nucleotides and their analogs. If present, modifications to the nucleotide structure can be imparted before or after assembly of the polymer. The sequence of nucleotides can be interrupted by non-nucleotide components. A polynucleotide can be further modified after polymerization, such as by conjugation with a labeling component. Other types of modifications include, for example, "caps," substitution of one or more of the naturally occurring nucleotides with analogs, internucleotide modifications, such as those containing uncharged linkages (e.g., methylphosphonates, phosphotriesters, phosphoamidates, carbamates, etc.) and those containing charged linkages (e.g., phosphorothioates, phosphodithioates, etc.), those containing pendant moieties such as proteins (e.g., nucleic acid enzymes, toxins, antibodies, signal peptides, ply-L-lysine, etc.), those containing intercalating agents (e.g., acridine, psoralens, etc.), those containing chelating agents (e.g., metals, radioactive metals, boron, metal oxides, etc.), those containing alkylating agents, those containing modified linkages (e.g., alpha-anomeric nucleic acids, etc.), and unmodified form(s) of polynucleotides. Additionally, any of the hydroxyl groups normally present on the sugar can be replaced, for example, by a phosphonate group, a phosphate group, protected by a standard protecting group, or activated to prepare additional linkages to additional nucleotides, or conjugated to a solid support. The 5' and 3' terminal OH can be phosphorylated or substituted with amines or organic capping group moieties of 1 to 20 carbon atoms. Other hydroxyls can also be derivatized to standard protecting groups.Polynucleotides can also contain analogous forms of ribose or deoxyribose sugars commonly known in the art, including, for example, 2'-O-methyl-, 2'-O-allyl, 2'-fluoro-, or 2'-azido-ribose, carbocyclic sugar analogs, α-anomeric sugars, epimeric sugars such as arabinose, xylose, or lyxose, pyranose sugars, furanose sugars, sedoheptulose, acyclic analogs, and abasic nucleoside analogs such as methyl riboside. One or more phosphodiester linkages can be replaced by alternative linking groups. These alternative linking groups include, but are not limited to, embodiments in which phosphate is replaced by P(O)S ("thioate"), P(S)S ("dithioate"), (O)NR2 ("amidate"), P(O)R, P(O)OR', CO, or CH2 ("formacetal"), where each R or R' is independently H or optionally a substituted or unsubstituted alkyl (1-20C), including an ether (--O--) linkage, aryl, alkenyl, cycloalkyl, cycloalkenyl, or araldyl. Not all linkages in a polynucleotide need be identical. The foregoing description applies to all polynucleotides referred to herein, including RNA and DNA.

[0210] The term "vector" refers to a construct that is capable of delivering and, optionally, expressing, one or more gene(s) or sequence(s) of interest in a host cell. Examples of vectors include, but are not limited to, viral vectors, naked DNA or RNA expression vectors, plasmids, cosmids, or phage vectors, DNA or RNA expression vectors associated with cationic condensing agents, DNA or RNA expression vectors encapsulated in liposomes, and certain eukaryotic cells such as producer cells.

[0211] The terms "polypeptide," "peptide," and "protein" are used interchangeably herein to refer to polymers of amino acids of any length. A polymer can be linear or branched, can comprise modified amino acids, and can be interrupted by non-amino acids. These terms also encompass amino acid polymers that are modified naturally or by intervention, for example, by disulfide bond formation, glycosylation, lipidation, acetylation, phosphorylation, or any other manipulation or modification, such as conjugation with a labeling component. Also included within the definition are, for example, polypeptides containing one or more analogs of an amino acid (including, for example, unnatural amino acids), as well as other modifications known in the art. Because the polypeptides of the present disclosure are based on antibodies, it is understood that in certain embodiments, the polypeptides can occur as single chains or associated chains.

[0212] The term "identical" or "percent identity" in the context of two or more nucleic acids or polypeptides refers to two or more sequences or subsequences that are the same or have a specified percentage of nucleotides or amino acid residues that are the same when compared and aligned for maximum correspondence (introducing gaps, if necessary), without considering any conservative amino acid substitutions as part of the sequence identity. Percent identity can be measured using sequence comparison software or algorithms or by visual inspection. A variety of algorithms and software are known in the art that can be used to obtain alignment of amino acid or nucleotide sequences. One such non-limiting example of a sequence alignment algorithm is the algorithm described in Karlin et al., Proc. Natl. Acad. Sci., 87:2264-2268 (1990), as modified in Karlin et al., Proc. Natl. Acad. Sci., 90:5873-5877 (1993), and incorporated into the NBLAST and XBLAST programs (Altschul et al., Nucleic Acids Res., 25:3389-3402 (1991)). In certain embodiments, gapped BLAST can be used as described in Altschul et al., Nucleic Acids Res. 25:3389-3402 (1997). BLAST-2, WU-BLAST-2 (Altschul et al., Methods in Enzymology, 266:460-480 (1996)), ALIGN, ALIGN-2 (Genentech, South San Francisco, Calif.), or Megalign (DNASTAR) are additional publicly available software programs that can be used to align sequences. In certain embodiments, the percent identity between two nucleotide sequences is determined using the GAP program of the GCG software (e.g., using the NWSgapdna.CMP matrix and a gap weight of 40, 50, 60, 70, or 90, and a length weight of 1, 2, 3, 4, 5, or 6).In certain alternative embodiments, the percent identity between two amino acid sequences can be determined using the GAP program in the GCG software package, which incorporates the Needleman and Wunsch algorithm (J. Mol. Biol. (48): 444-453 (1970)) (e.g., using either a Blossum 62 matrix or a PAM250 matrix, and gap weights of 16, 14, 12, 10, 8, 6, or 4, and length weights of 1, 2, 3, 4, or 5). Alternatively, in certain embodiments, percent identity between nucleotide or amino acid sequences is determined using the Myers and Miller algorithm (CABIOS, 4: 11-17 (1989)). For example, percent identity can be determined using the ALIGN program (version 2.0) and PAM120 with a residue table, a gap length penalty of 12, and a gap penalty of 4. Appropriate parameters for maximal alignment with particular alignment software can be determined by one of ordinary skill in the art. In certain embodiments, the default parameters of the alignment software are used. In certain embodiments, the percent identity "X" of a first amino acid sequence to a second sequence is calculated as 100 times (Y / Z), where Y is the number of amino acid residues scored as identical matches in the alignment of the first and second sequences (aligned by visual inspection or a specific sequence alignment program), and Z is the total number of residues in the second sequence. If the length of the first sequence is longer than that of the second sequence, the percent identity of the first sequence to the second sequence will be longer than the percent identity of the second sequence to the first sequence.

[0213] As a non-limiting example, whether any particular polynucleotide has a certain percent sequence identity to a reference sequence (e.g., at least 80% identical, at least 85% identical, at least 90% identical, and in some embodiments, at least 95%, 96%, 97%, 98%, or 99% identical) can, in certain embodiments, be determined using the Bestfit program (Wisconsin Sequence Analysis Package, Version 8 for Unix, Genetics Computer Group, University Research Park, 575 Science Drive, Madison, Wis. 53711). Bestfit uses the local homology algorithm of Smith and Waterman (Advances in Applied Mathematics 2:482-489 (1981)) to find the best segment of homology between two sequences. When using Bestfit or any other sequence alignment program to determine whether a particular sequence is, for example, 95% identical to a reference sequence according to the present disclosure, parameters are set such that the percentage of identity is calculated over the entire length of the reference nucleotide sequence and gaps in homology of up to 5% of the total number of nucleotides in the reference sequence are allowed.

[0214] In some embodiments, two nucleic acids or polypeptides of the present disclosure are substantially identical, meaning that when compared and aligned for maximum correspondence, they have at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, and in some embodiments, at least 95%, 96%, 97%, 98%, or 99% nucleotide or amino acid residue identity, as measured using a sequence comparison algorithm or by visual inspection. Identity can exist over a region of the sequences that is at least about 10, about 20, about 40-60 residues in length, or any integral value therebetween, and can extend over a region longer than 60-80 residues, e.g., at least about 90-100 residues; in some embodiments, the sequences are substantially identical over the entire length of the sequences being compared, e.g., the coding regions of the nucleotide sequences.

[0215] "Conservative amino acid substitution" refers to the replacement of one amino acid residue with another amino acid residue having a similar side chain. A family of amino acid residues with similar side chains has been defined in the art, including basic side chains (e.g., lysine, arginine, histidine), acidic side chains (e.g., aspartic acid, glutamic acid), uncharged polar side chains (e.g., glycine, asparagine, glutamine, serine, threonine, tyrosine, cysteine), nonpolar side chains (e.g., alanine, valine, leucine, isoleucine, proline, phenylalanine, methionine, tryptophan), β-branched side chains (e.g., threonine, valine, isoleucine), and aromatic side chains (e.g., tyrosine, phenylalanine, tryptophan, histidine). For example, the substitution of phenylalanine for tyrosine is a conservative substitution. In some embodiments, conservative substitutions in the sequences of the polypeptides and antibodies of the present disclosure do not abolish binding of an antibody containing an amino acid sequence to an antigen(s), e.g., VISTA, to which the antibody binds. Methods for identifying conservative nucleotide and amino acid substitutions that do not eliminate antigen binding are well known in the art (see, e.g., Brummell et al., Biochem. 32:1180-1 187 (1993); Kobayashi et al., Protein Eng. 12(10):879-884 (1999); and Burks et al., Proc. Natl. Acad. Sci. USA 94:412-417 (1997)).

[0216] As used herein, "substantially pure" refers to a material that is at least 50% pure (i.e., free from contaminants), more preferably at least 90% pure, more preferably at least 95% pure, more preferably at least 98% pure, and more preferably at least 99% pure.

[0217] A "host cell" includes an individual cell or cell culture that can be or has been the recipient of a vector(s) for incorporation of a polynucleotide insert. A host cell includes the progeny of a single host cell, and the progeny may not necessarily be completely identical (in morphology or genomic DNA complement) to the original parent cell due to natural, accidental, or deliberate mutation. A host cell includes cells transfected in vivo with a polynucleotide(s) of the invention.

[0218] The term "Fc region" is used to define the C-terminal region of an immunoglobulin heavy chain. An "Fc region" may be a native-sequence Fc region or a variant Fc region. Although the boundaries of the Fc region of an immunoglobulin heavy chain can vary, the human IgG heavy chain Fc region is usually defined to stretch from the amino acid residue at position Cys226, or from Pro230, to the carboxyl terminus. The numbering of residues within the Fc region is that of the EU index, as in Kabat. Kabat et al., Sequences of Proteins of Immunological Interest, 5th Ed. Public Health Service, National Institutes of Health, Bethesda, Md., 1991. The Fc region of an immunoglobulin generally comprises two constant domains, CH2 and CH3.

[0219] As used herein, "Fc receptor" and "FcR" refer to a receptor that binds to the Fc region of an antibody. A preferred FcR is a native-sequence human FcR. Additionally, a preferred FcR is one that binds IgG antibodies (gamma receptors), including receptors of the FcγRI, FcγRII, and FcγRII subclasses, including allelic variants and alternatively spliced ​​forms of these receptors. FcγRII receptors include FcγRIIA (an "activating receptor") and FcγRIIB (an "inhibiting receptor"), which have similar amino acid sequences that differ primarily in their cytoplasmic domains. FcRs have been reviewed in Ravetch and Kinet, 1991, Ann. Rev. Immunol., 9:457-92; Capel et al., 1994, ImmunoMethods, 4:25-34; and de Haas et al., 1995, J. Lab. Clin. Med., 126:330-41. "FcR" also includes the neonatal receptor FcRn, which is involved in the transfer of maternal IgG to the fetus (Guyer et al., 1976, J. Immunol., 117:587; and Kim et al., 1994, J. Immunol., 24:249).

[0220] "Complement-dependent cytotoxicity" and "CDC" refer to the lysis of a target in the presence of complement. The complement activation pathway is initiated by the binding of the first component of the complement system (C1q) to a molecule (e.g., an antibody) complexed with a cognate antigen. To assess complement activation, a CDC assay, for example, as described in Gazzano-Santoro et al., J. Immunol. Methods, 202:163 (1996), can be performed.

[0221] A "functional Fc region" possesses at least one effector function of a native sequence Fc region. Exemplary "effector functions" include, but are not limited to, C1q binding, complement-dependent cytotoxicity (CDC), Fc receptor binding, antibody-dependent cell-mediated cytotoxicity (ADCC), phagocytosis, down-regulation of cell surface receptors (e.g., B cell receptor, BCR), etc. Such effector functions generally require that the Fc region be combined with a binding domain (e.g., an antibody variable domain), and may be assessed using a variety of assays known in the art for assessing such antibody effector functions.

[0222] A "native-sequence Fc region" comprises an amino acid sequence identical to the amino acid sequence of an Fc region found in nature. A "variant Fc region" comprises an amino acid sequence that differs from that of a native-sequence Fc region by virtue of at least one amino acid modification, yet retains at least one effector function of the native-sequence Fc region. Preferably, the variant Fc region comprises at least one amino acid substitution, e.g., about one to about ten amino acid substitutions, preferably about one to about five amino acid substitutions, within the native-sequence Fc region or within the Fc region of the parent polypeptide, compared to the native-sequence Fc region or the Fc region of the parent polypeptide. The variant Fc region herein will preferably retain at least about 80% sequence identity with the native-sequence Fc region and / or the Fc region of the parent polypeptide, most preferably at least about 90% sequence identity thereto, and more preferably at least about 95%, at least about 96%, at least about 97%, at least about 98%, or at least about 99% sequence identity thereto.

[0223] As used herein, "antibody-dependent cell-mediated cytotoxicity" and "ADCC" refer to a cell-mediated reaction in which nonspecific cytotoxic cells expressing Fc receptors (FcRs) (e.g., natural killer (NK) cells, neutrophils, and macrophages) recognize bound antibodies on target cells and subsequently cause lysis of the target cells. ADCC activity of a molecule of interest can be assessed using an in vitro ADCC assay, such as that described in U.S. Pat. No. 5,500,362 or U.S. Pat. No. 5,821,337. Useful effector cells for such assays include peripheral blood mononuclear cells (PBMCs) and NK cells. Alternatively, or in addition, ADCC activity of a molecule of interest can be assessed in vivo, for example, in an animal model disclosed in Clynes et al., 1998, PNAS (USA), 95:652-656.

[0224] In this disclosure, the term "halo" when used alone or as part of another group refers to -Cl, -F, -Br, or -I. For example, halo is -Cl or -F.

[0225] As used herein, the term "hydroxy" when used alone or as part of another group refers to --OH.

[0226] In this disclosure, the term "thiol" or "sulfhydryl" when used alone or as part of another group refers to --SH.

[0227] In this disclosure, the term "alkyl" when used alone or as part of another group refers to an unsubstituted straight or branched chain aliphatic hydrocarbon containing 1 to 12 carbon atoms, i.e., C 1~12 Alkyl or a specified number of carbon atoms, e.g., C1 alkyl such as methyl, C2 alkyl such as ethyl, C3 alkyl such as propyl or isopropyl, C4 alkyl such as methyl, ethyl, propyl, or isopropyl 1~3 For example, alkyl refers to C 1~10 In another example, alkyl is C1~6 In another example, alkyl is C 1~4 In another example, the alkyl is a straight chain C1-10 alkyl. In another example, the alkyl is a branched C 3~10 In another example, the alkyl is a straight chain C 1~6 In another example, the alkyl is a branched C 3~6 In another example, the alkyl is a straight chain C 1~4 In another example, the alkyl is a branched C 3~4 In another example, alkyl is a straight or branched chain C 3~4 Non-limiting exemplary C 1~10 Alkyl groups include methyl, ethyl, propyl, isopropyl, butyl, sec-butyl, tert-butyl, iso-butyl, 3-pentyl, hexyl, heptyl, octyl, nonyl, and decyl. 1~4 Alkyl groups include methyl, ethyl, propyl, isopropyl, butyl, sec-butyl, tert-butyl, and isobutyl.

[0228] In the present disclosure, the term "optionally substituted alkyl," when used alone or as part of another group, refers to an aryl that is either unsubstituted or substituted with one, two, or three substituents independently selected from the group consisting of nitro, hydroxy, cyano, haloalkoxy, aryloxy, alkylthio, sulfonamido, alkylcarbonyl, arylcarbonyl, alkylsulfonyl, arylsulfonyl, carboxy, carboxamido, alkoxycarbonyl, thiol, --N(H)C(=O)NH, and --N(H)C=NH)NH, optionally substituted aryl, and optionally substituted heteroaryl. For example, the optionally substituted alkyl is substituted with two substituents. In another example, the optionally substituted alkyl is substituted with one substituent. In another example, the optionally substituted alkyl is unsubstituted. Non-limiting exemplary substituted alkyl groups include --CH2OH, --CH2SH, --CH2Ph, --CH2(4-OH)Ph, --CH2(imidazolyl), --CH2CH2CO2H, --CH2CH2SO2CH3, --CH2CH2COPh, and --CH2OC(=O)CH3.

[0229] In this disclosure, the term "cycloalkyl" when used alone or as part of another group refers to an unsubstituted saturated or partially unsaturated cyclic aliphatic hydrocarbon containing, for example, one to three rings having 3 to 12 carbon atoms, including one or two double bonds, i.e., C 3~12 cycloalkyl, or one having a specified number of carbon atoms. In one example, the cycloalkyl has two rings. In another example, the cycloalkyl has one ring. In another example, the cycloalkyl is saturated. In another example, the cycloalkyl is unsaturated. In another example, the cycloalkyl is C 3~8 In another example, cycloalkyl is C 3~6Cycloalkyl. The term "cycloalkyl" is intended to include groups in which the ring --CH-- is replaced with --C(=O)--. Non-limiting exemplary cycloalkyl groups include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, norbornyl, decalin, adamantyl, cyclohexenyl, cyclopentenyl, and cyclopentanone.

[0230] In this disclosure, the term "optionally substituted cycloalkyl" when used alone or as part of another group refers to a cycloalkyl that is either unsubstituted or substituted with one, two, or three substituents independently selected from halo, nitro, cyano, hydroxy, alkylcarbonyloxy, cycloalkylcarbonyloxy, amino, haloalkyl, hydroxyalkyl, alkoxy, haloalkoxy, aryloxy, aralkyloxy, alkylthio, carboxamido, sulfonamido, alkylcarbonyl, arylcarbonyl, alkylsulfonyl, arylsulfonyl, carboxy, carboxyalkyl, optionally substituted alkyl, optionally substituted cycloalkyl, alkenyl, alkynyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted heterocyclo, alkoxyalkyl,)amino)alkyl, (carboxamido)alkyl, (heterocyclo)alkyl, and -OC(=O)-amino. The term "optionally substituted cycloalkyl" includes a cycloalkyl group having a fused, optionally substituted aryl, such as phenyl, or a fused, optionally substituted heteroaryl, such as pyridyl. An optionally substituted cycloalkyl having a fused, optionally substituted aryl or a fused, optionally substituted heteroaryl group can be attached to the rest of the molecule at any available carbon atom on the cycloalkyl ring. In one example, the optionally substituted cycloalkyl is substituted with two substituents. In another example, the optionally substituted cycloalkyl is substituted with one substituent. In another example, the optionally substituted cycloalkyl is unsubstituted.

[0231] In this disclosure, the term "aryl" when used alone or as part of another group refers to an unsubstituted monocyclic or bicyclic aromatic ring system having 6 to 14 carbon atoms, i.e., C 6~14"aryl" refers to aryl. Non-limiting exemplary aryl groups include phenyl (abbreviated as "Ph"), naphthyl, phenanthryl, anthracyl, indenyl, azulenyl, biphenyl, biphenylenyl, and fluorenyl groups. In one example, the aryl group is phenyl or naphthyl.

[0232] In this disclosure, the term "optionally substituted aryl," as used herein alone or as part of another group, refers to an aryl that is either unsubstituted or substituted with 1 to 5 substituents independently selected from halo, nitro, cyano, hydroxy, thiol, amino, alkylamino, dialkylamino, optionally substituted alkyl, haloalkyl, hydroxyalkyl, alkoxy, haloalkoxy, aryloxy, aralkyloxy, alkylthio, carboxamido, sulfonamido, alkylcarbonyl, arylcarbonyl, alkylsulfonyl, haloalkylsulfonyl, cycloalkylsulfonyl, (cycloalkyl)alkylsulfonyl, arylsulfonyl, heteroarylsulfonyl, heterocyclosulfonyl, carboxy, carboxyalkyl, optionally substituted cycloalkyl, alkenyl, alkynyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted heterocyclo, alkoxycarbonyl, alkoxyalkyl, (amino)alkyl, (carboxamido)alkyl, and (heterocyclo)alkyl.

[0233] In one example, the optionally substituted aryl is an optionally substituted phenyl. In another example, the optionally substituted phenyl has four substituents. In another example, the optionally substituted phenyl has three substituents. In another example, the optionally substituted phenyl has two substituents. In another example, the optionally substituted phenyl has one substituent. In another example, the optionally substituted phenyl is unsubstituted. Non-limiting exemplary substituted aryl groups include 2-methylphenyl, 2-methoxyphenyl, 2-fluorophenyl, 2-chlorophenyl, 2-bromophenyl, 3-methylphenyl, 3-methoxyphenyl, 3-fluorophenyl, 3-chlorophenyl, 4-methylphenyl, 4-ethylphenyl, 4-methoxyphenyl, 4-fluorophenyl, 4-chlorophenyl, 2,6-difluorophenyl, 2,6-dichlorophenyl, 2-methyl, 3-methoxyphenyl, 2-ethyl, 3-methoxyphenyl, 3,4-dimethoxyphenyl, 3,5-difluorophenyl, 3,5-dimethoxyphenyl, 3,5-dimethoxy, 4-methylphenyl, 2-fluoro-3-chlorophenyl, 3-chloro-4-fluorophenyl, 4-(pyridin-4-ylsulfonyl)phenyl. The term optionally substituted aryl includes a phenyl group having a fused optionally substituted cycloalkyl or a fused optionally substituted heterocyclo group. An optionally substituted phenyl having a fused optionally substituted cycloalkyl or a fused optionally substituted heterocyclo group can be attached to the remainder of the molecule at any available carbon atom on the phenyl ring.

[0234] In this disclosure, the term "alkenyl," when used alone or as part of another group, refers to an alkyl containing one, two, or three carbon-carbon double bonds. In one example, an alkenyl has one carbon-carbon double bond. In another example, an alkenyl has a C 2~6 In another example, the alkenyl is C 2~4Alkenyl. Non-limiting exemplary alkenyl groups include ethenyl, propenyl, isopropenyl, butenyl, sec-butenyl, pentenyl, and hexenyl.

[0235] In this disclosure, the term "optionally substituted alkenyl," as used herein alone or as part of another group, refers to an alkenyl that is either unsubstituted or substituted with one, two, or three substituents independently selected from the group consisting of halo, nitro, cyano, hydroxy, amino, alkylamino, dialkylamino, haloalkyl, hydroxyalkyl, alkoxy, haloalkoxy, aryloxy, aralkyloxy, alkylthio, carboxamido, sulfonamido, alkylcarbonyl, arylcarbonyl, alkylsulfonyl, arylsulfonyl, carboxy, carboxyalkyl, optionally substituted alkyl, optionally substituted cycloalkyl, alkenyl, alkynyl, optionally substituted aryl, heteroaryl, and optionally substituted heterocyclo.

[0236] In this disclosure, the term "alkynyl" when used alone or as part of another group refers to an alkyl containing 1 to 3 carbon-carbon triple bonds. In one example, an alkynyl has one carbon-carbon triple bond. In another example, an alkynyl is C 2~6 In another example, the alkynyl is C 2~4 Alkynyl. Non-limiting exemplary alkynyl groups include ethynyl, propynyl, butynyl, 2-butynyl, pentynyl, and hexynyl groups.

[0237] In this disclosure, the term "optionally substituted alkynyl" as used herein alone or as part of another group refers to an alkynyl that is either unsubstituted or substituted with one, two, or three substituents independently selected from the group consisting of halo, nitro, cyano, hydroxy, amino, alkylamino, dialkylamino, haloalkyl, hydroxyalkyl, alkoxy, haloalkoxy, aryloxy, aralkyloxy, alkylthio, carboxamido, sulfonamido, alkylcarbonyl, arylcarbonyl, alkylsulfonyl, arylsulfonyl, carboxy, carboxyalkyl, optionally substituted alkyl, cycloalkyl, alkenyl, alkynyl, optionally substituted aryl, optionally substituted heteroaryl, and heterocyclo.

[0238] In this disclosure, the term "haloalkyl," when used alone or as part of another group, refers to an alkyl substituted with one or more fluorine, chlorine, bromine, and / or iodine atoms. In one example, the alkyl group is substituted with one, two, or three fluorine and / or chlorine atoms. In another example, a haloalkyl group is a C 1~4 Haloalkyl groups. Non-limiting exemplary haloalkyl groups include fluoromethyl, 2-fluoroethyl, difluoromethyl, trifluoromethyl, pentafluoroethyl, 1,1-difluoroethyl, 2,2-difluoroethyl, 2,2,2-trifluoroethyl, 3,3,3-trifluoropropyl, 4,4,4-trifluorobutyl, and trichloromethyl groups.

[0239] In this disclosure, the term "alkoxy" when used alone or as part of another group refers to an optionally substituted alkyl, optionally substituted cycloalkyl, optionally substituted alkenyl, or optionally substituted alkynyl attached to a terminal oxygen atom. In one example, the alkoxy is an optionally substituted alkyl attached to a terminal oxygen atom. In one example, an alkoxy group is a C attached to a terminal oxygen atom.1~6 In another example, an alkoxy group is a C attached to a terminal oxygen atom. 1~4 Alkyl. Non-limiting exemplary alkoxy groups include methoxy, ethoxy, and tert-butoxy.

[0240] In this disclosure, the term "alkylthio" when used alone or as part of another group refers to an optionally substituted alkyl attached to a terminal sulfur atom. In one example, an alkylthio group is C 1~4 It is an alkylthio group. Non-limiting exemplary alkylthio groups include --SCH3 and --SCH2CH3.

[0241] In this disclosure, the term "haloalkoxy" when used alone or as part of another group refers to a haloalkyl attached to a terminal oxygen atom. Non-limiting exemplary haloalkoxy groups include fluoromethoxy, difluoromethoxy, trifluoromethoxy, and 2,2,2-trifluoroethoxy.

[0242] In the present disclosure, the term "heteroaryl" refers to unsubstituted monocyclic and bicyclic aromatic ring systems having 5 to 14 ring atoms, i.e., 5- to 14-membered heteroaryls, in which at least one carbon atom of one of the rings is replaced with a heteroatom independently selected from the group consisting of oxygen, nitrogen, and sulfur. In one example, a heteroaryl contains one, two, three, or four heteroatoms independently selected from the group consisting of oxygen, nitrogen, and sulfur. In one example, a heteroaryl has three heteroatoms. In another example, a heteroaryl has two heteroatoms. In another example, a heteroaryl has one heteroatom. In another example, a heteroaryl is a 5- to 10-membered heteroaryl. In another example, a heteroaryl is a 5- or 6-membered heteroaryl. In another example, a heteroaryl has five ring atoms, such as thienyl, a 5-membered heteroaryl having four carbon atoms and one sulfur atom. In another example, heteroaryl has six ring atoms, e.g., pyridyl, which is a six-membered heteroaryl having five carbon atoms and one nitrogen atom. Non-limiting exemplary heteroaryl groups include thienyl, benzo[b]thienyl, naphtho[2,3-b]thienyl, thianthrenyl, furyl, benzofuryl, pyranyl, isobenzofuranyl, benzoxazolyl, chromenyl, xanthenyl, 2H-pyrrolyl, pyrrolyl, imidazolyl, pyrazolyl, pyridyl, pyrazinyl, pyrimidinyl, pyridazinyl, isoindolyl, 3H-indolyl, and indolyl. , indazolyl, purinyl, isoquinolyl, quinolyl, phthalazinyl, naphthyridinyl, cinnolinyl, quinazolinyl, pteridinyl, 4aH-carbazolyl, carbazolyl, β-carbolinyl, phenanthridinyl, acridinyl, pyrimidinyl, phenanthrolinyl, phenazinyl, thiazolyl, isothiazolyl, phenothiazolyl, isoxazolyl, furazanyl, and phenoxazinyl.In one example, heteroaryl is thienyl (e.g., thien-2-yl and thien-3-yl), furyl (e.g., 2-furyl and 3-furyl), pyrrolyl (e.g., 1H-pyrrol-2-yl and 1H-pyrrol-3-yl), imidazolyl (e.g., 2H-imidazol-2-yl and 2H-imidazol-4-yl), pyrazolyl (e.g., 1H-pyrazol-3-yl, 1H-pyrazol-4-yl and 1H-pyrazol-5-yl), pyridyl (e.g., pyridin-2-yl, pyridin-3-yl, and pyridin-4-yl), pyrimidinyl (e.g., pyrimidin-2-yl, The heteroaryl group is selected from the group consisting of pyrimidin-4-yl and pyrimidin-5-yl), thiazolyl (e.g., thiazol-2-yl, thiazol-4-yl, and thiazol-5-yl), isothiazolyl (e.g., isothiazol-3-yl, isothiazol-4-yl, -5-yl), oxazolyl (e.g., oxazol-2-yl, oxazol-4-yl, and oxazol-5-yl), isoxazolyl (e.g., isoxazol-3-yl, isoxazol-4-yl, and isoxazol-5-yl), and indazolyl (e.g., 1H-indazol-3-yl). The term "heteroaryl" is also intended to include possible N-oxides. A non-limiting exemplary N-oxide is pyridyl N-oxide.

[0243] In one example, the heteroaryl is a 5- or 6-membered heteroaryl. In one example, the heteroaryl is a 5-membered heteroaryl, i.e., the heteroaryl is a monocyclic aromatic ring system having 5 ring atoms, and at least one carbon atom in the ring is independently replaced with a heteroatom selected from nitrogen, oxygen, and sulfur. Non-limiting exemplary 5-membered heteroaryl groups include thienyl, furyl, pyrrolyl, oxazolyl, pyrazolyl, imidazolyl, thiazolyl, isothiazolyl, and isoxazolyl. In another example, the heteroaryl is a 6-membered heteroaryl, for example, the heteroaryl is a monocyclic aromatic ring system having 6 ring atoms, and at least one carbon atom in the ring is replaced with a nitrogen atom. Non-limiting exemplary 6-membered heteroaryl groups include pyridyl, pyrazinyl, pyrimidinyl, and pyridazinyl.

[0244] In this disclosure, the term "optionally substituted heteroaryl" when used alone or as part of another group refers to heteroaryl that is either unsubstituted or substituted with 1, 2, 3, or 4 substituents independently selected from halo, nitro, cyano, hydroxy, amino, alkylamino, dialkylamino, haloalkyl, hydroxyalkyl, alkoxy, haloalkoxy, aryloxy, aralkyloxy, alkylthio, carboxamido, sulfonamido, alkylcarbonyl, arylcarbonyl, alkylsulfonyl, haloalkylsulfonyl, cycloalkylsulfonyl, (cycloalkyl)alkylsulfonyl, arylsulfonyl, heteroarylsulfonyl, carboxy, carboxyalkyl, optionally substituted alkyl, optionally substituted cycloalkyl, alkenyl, alkynyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted heterocyclo, alkoxyalkyl, (amino)alkyl, (carboxamido)alkyl, and (heterocyclo)alkyl. In one example, the optionally substituted heteroaryl has one substituent. In another example, the optionally substituted heteroaryl is unsubstituted. Any available carbon or nitrogen atom can be substituted. The term optionally substituted heteroaryl includes a heteroaryl group having a fused, optionally substituted cycloalkyl or a fused, optionally substituted heterocyclo group. An optionally substituted heteroaryl having a fused, optionally substituted cycloalkyl or a fused, optionally substituted heterocyclo group can be attached to the rest of the molecule at any available carbon atom on the heteroaryl ring.

[0245] In this disclosure, the term "heterocyclo" when used alone or as part of another group refers to an unsubstituted saturated or partially unsaturated cyclic group, i.e., a 3- to 14-membered heterocyclo, containing, for example, one, two, or three rings having 3 to 14 ring members, including one or two double bonds, in which at least one carbon atom of one of the rings is replaced with a heteroatom. Each heteroatom is independently selected from the group consisting of oxygen, sulfur, including sulfoxide and sulfone, and / or nitrogen atoms, which may be oxidized or quaternized. The term "heterocyclo" also includes groups in which the ring --CH-- is replaced with --C(=O)--, for example, cyclic ureido groups such as 2-imidazolidinone, and cyclic amide groups such as β-lactam, γ-lactam, δ-lactam, ε-lactam, and piperazin-2-one. The term "heterocyclo" also includes groups having a fused, optionally substituted aryl group, such as indolinyl or chroman-4-yl. In one embodiment, a heterocyclo group is 4~6 Heterocyclos are 4-, 5-, or 6-membered ring groups containing one ring and one or two oxygen and / or nitrogen atoms. In one embodiment, a heterocyclo group is a C 4~6 Heterocyclo is a heterocyclo. The heterocyclo can be optionally attached to the remainder of the molecule through any available carbon or nitrogen atom. Non-limiting exemplary heterocyclo groups include azetidinyl, dioxanyl, tetrahydropyranyl, 2-oxopyrrolidin-3-yl, piperazin-2-one, piperazine-2,6-dione, 2-imidazolidinone, piperidinyl, morpholinyl, piperazinyl, pyrrolidinyl, and indolinyl.

[0246] In this disclosure, the term "optionally substituted heterocyclo" as used herein alone or as part of another group refers to a heterocyclo that is either unsubstituted or substituted with one, two, three, or four substituents independently selected from halo, nitro, cyano, hydroxy, amino, alkylamino, dialkylamino, haloalkyl, hydroxyalkyl, alkoxy, haloalkoxy, aryloxy, aralkyloxy, alkylthio, carboxamido, sulfonamido, alkylcarbonyl, cycloalkylcarbonyl, alkoxycarbonyl, CFC(=O)--, arylcarbonyl, alkylsulfonyl, arylsulfonyl, carboxy, carboxyalkyl, alkyl, optionally substituted cycloalkyl, alkenyl, alkynyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted heterocyclo, alkoxyalkyl, (amino)alkyl, (carboxamido)alkyl, or (heterocyclo)alkyl. Substitution can occur on any available carbon or nitrogen atom, or both.

[0247] In this disclosure, the term "amino" when used alone or as part of another group refers to a group of the formula --NRO a R b where R a and R b are each independently selected from the group consisting of hydrogen, optionally substituted alkyl, and aralkyl, or R a and R b taken together form a 3-8 membered optionally substituted heterocycle. Non-limiting exemplary amino groups include --NH2 and --N(H)(CH3).

[0248] As used herein, the term "carboxamide" when used alone or as part of another group refers to a group of the formula --C(.dbd.O)NR. a R b where R a and R bare each independently selected from the group consisting of hydrogen, optionally substituted alkyl, hydroxyalkyl, and optionally substituted aryl, optionally substituted heterocyclo, and optionally substituted heteroaryl, or R a and R b taken together with the nitrogen to which they are attached form a 3- to 8-membered optionally substituted heterocyclo group. In one embodiment, R a and R b Each is independently hydrogen or optionally substituted alkyl. In one embodiment, R a and R b taken together with the nitrogen to which they are attached form a 3- to 8-membered optionally substituted heterocyclo group. Non-limiting exemplary carboxamide groups include --CONH, --CON(H)CH, and --CON(CH).

[0249] In this disclosure, the term "alkoxycarbonyl" when used alone or as part of another group refers to a carbonyl group, i.e., -C(=O)-, substituted with alkoxy. In one embodiment, alkoxy is C 1~4 Non-limiting exemplary alkoxycarbonyl groups include --C(.dbd.O)OMe, --C(.dbd.O)OEt, and --C(.dbd.O)OtBu.

[0250] In this disclosure, the term "carboxy" when used alone or as part of another group refers to a radical of formula --CO.sub.2H.

[0251] In the present disclosure, the term "self-immolative group" or "sacrificial group" or "sacrificial linker" refers to all or part of a cleavable linker, including bifunctional chemical moieties, e.g., glucocorticosteroids of Formula I, II, or III, that are capable of covalently linking two spaced-apart chemical moieties to a normally stable tripartite molecule, releasing one of the spaced-apart chemical moieties from the tripartite molecule upon enzymatic cleavage, and spontaneously cleaving from the remainder of the molecule to release the other spaced-apart chemical moiety following enzymatic cleavage. In some embodiments, the sacrificial linker comprises a p-aminobenzyl unit. In some such embodiments, p-aminobenzyl alcohol is attached to the amino acid unit via an amide bond, and a carbamate, methylcarbamate, or carbonate is made between the benzyl alcohol and the drug (Hamann et al. (2005) Expert Opin. Ther. Patents (2005) 15:1087-1103). In some embodiments, the sacrificial linker is p-aminobenzyloxycarbonyl (PAB) (see Example 3 and the Exemplary Embodiments section of this application).

[0252] In the present disclosure, the term "protecting group" or "PG" refers to a group that blocks, i.e., protects, a functionality, such as an amine functionality, while reactions are carried out on other functional groups or portions of a molecule. Those skilled in the art will be familiar with the selection, attachment, and cleavage of amine protecting groups and will understand that many different protecting groups are known in the art, and that the suitability of one protecting group or another will depend on the particular synthetic scheme planned. Treatises on this subject, such as Wuts, PGM; Greene, TW, "Greene's Protective Groups in Organic Synthesis," 4th Ed., J. Wiley & Sons, NY, 2007, are available for reference. Suitable protecting groups include carbobenzyloxy (Cbz), tert-butyloxycarbonyl (BOC), 9-fluorenylmethyloxycarbonyl (FMOC), and benzyl (Bn) groups. In one embodiment, the protecting group is a BOC group.

[0253] In this disclosure, the term "ethylene glycol" refers to a chemical of the formula -OCH2CH2O-.

[0254] In this disclosure, the term "ethylene oxide" refers to a chemical compound of formula -CH2CH2O-.

[0255] As used in this disclosure and claims, the singular forms "a," "an," and "the" include the plural forms unless the context clearly dictates otherwise.

[0256] Whenever an embodiment is described herein with the term "comprising," it is understood that otherwise similar embodiments described with the terms "consisting of" and / or "consisting essentially of" are also provided.

[0257] The term "and / or" as used herein in phrases such as "A and / or B" is intended to include both "A and B," "A or B," "A," and "B." Similarly, the term "and / or" as used in phrases such as "A, B, and / or C" is intended to include each of the following embodiments: A, B, and C; A, B, or C; A or C; A or B; B or C; A and C; A and B; B and C; A (alone); B (alone); and C (alone).

[0258] As used herein, "autoimmunity" or "autoimmune disease or condition" refers broadly to and includes diseases or disorders arising from and directed against an individual's own tissues or their co-isolates or manifestations, or conditions resulting therefrom. As used herein, autoimmune conditions include inflammatory or allergic conditions, e.g., chronic diseases characterized by a host immune response to self-antigens that are characterized by inflammation and / or potentially associated with tissue destruction, such as rheumatoid arthritis, for which steroids are an effective treatment.

[0259] An "allergic disease or condition" or "allergic reaction" is a condition caused by hypersensitivity of the immune system to typically harmless substances or antigens in the environment. These diseases include, by way of example only, atopic dermatitis, allergic asthma, primary immunodeficiency, chronic sinusitis, eosinophil-related diseases, and other conditions involving an allergic response or reaction.

[0260] "Immune cells," as used herein, refer broadly to cells that are of hematopoietic origin and play a role in the immune response, including, but not limited to, lymphocytes such as B cells and T cells, natural killer cells, dendritic cells, and myeloid cells such as monocytes, macrophages, eosinophils, mast cells, basophils, and granulocytes, among other immune cell types.

[0261] "Immune-related disease (or disorder or condition)" as used herein should be understood to encompass any disease, disorder, or condition selected from the group including, but not limited to, autoimmune diseases, inflammatory disorders, and immune disorders associated with transplant rejection of a graft, such as acute and chronic rejection of organ transplants, allogeneic stem cell transplants, autologous stem cell transplants, bone marrow transplants, and graft-versus-host disease.

[0262] As used interchangeably herein, the terms "inflammatory disorder," "inflammatory condition," and / or "inflammation" refer broadly to chronic or acute inflammatory diseases and explicitly include inflammatory autoimmune diseases and inflammatory allergic conditions. These conditions include, by way of example, inflammatory disorders characterized by dysregulated immune responses to harmful stimuli, such as pathogens, damaged cells, or irritants. Inflammatory diseases underlie a variety of human diseases. Non-immune diseases with an etiology related to inflammatory processes include cancer, atherosclerosis, and ischemic heart disease. Examples of inflammation-related disorders include chronic prostatitis, glomerulonephritis, hypersensitivity reactions, pelvic inflammatory disease, reperfusion injury, sarcoidosis, vasculitis, interstitial cystitis, normocomplementemic urticarial vasculitis, pericarditis, myositis, antisynthetase syndrome, scleritis, macrophage activation syndrome, Behcet's syndrome, PAPA syndrome, Blau syndrome, gout, adult and juvenile Still's disease, cryopyrin-associated periodic fever syndrome, Muckle-Wells syndrome, and familial cold-induced autoimmune disorders. autoinflammatory syndrome, neonatal-onset multisystem inflammatory disease, familial Mediterranean fever, chronic infantile neurological, cutaneous and joint syndrome, systemic juvenile idiopathic arthritis, hyper-IgD syndrome, Schnitzler's syndrome, TNF receptor-associated periodic syndrome (TRAPSP), gingivitis, periodontitis, hepatitis, cirrhosis, pancreatitis, myocarditis, vasculitis, gastritis, gout, gouty arthritis, and inflammatory skin disorders selected from psoriasis, atopic dermatitis, eczema, rosacea, urticaria, and acne.

[0263] As used herein, "mammal" broadly refers to any and all warm-blooded vertebrates of the mammalian species, including humans, characterized by a covering of hair on the skin and, in females, mammary glands that produce milk to feed their young. Examples of mammals include, but are not limited to, alpacas, armadillos, capybaras, cats, camels, chimpanzees, chinchillas, cows, dogs, goats, gorillas, hamsters, horses, humans, lemurs, llamas, mice, non-human primates, pigs, rats, sheep, shrews, squirrels, tapirs, and voles. Mammals include, but are not limited to, bovine, ovine, porcine, primate, and rodent species. Mammals also include any and all of the mammal species of the world listed by the Smithsonian National Museum of Natural History, Washington, D.C.

[0264] "Patient," or "subject," or "recipient," "individual," or "treated individual" are used interchangeably herein and refer broadly to any animal in need of treatment, either to alleviate a medical condition or to prevent the occurrence or recurrence of a medical condition. As used herein, "patient" also refers broadly to any animal that has risk factors, a medical history, susceptibility, symptoms, and signs, has been previously diagnosed, is at risk for a disease, or is a member of a patient population for a disease. A patient can be a clinical patient, such as a human, or a veterinary patient, such as a pet, livestock, farm animal, exotic animal, or zoo animal.

[0265] As used herein, a "subject" or "patient" or "individual" in the context of therapy or diagnosis includes any human or non-human animal. The term "non-human animal" includes all vertebrates, e.g., mammals and non-mammals, such as non-human primates, sheep, dogs, cats, horses, cows, chickens, amphibians, reptiles, etc.; i.e., any animal suitable for treatment according to the present invention includes, but is not limited to, avian and mammalian subjects, preferably mammals. Any mammalian subject in need of treatment according to the present invention is suitable. Human subjects of both genders and at any stage of development (i.e., neonate, infant, juvenile, adolescent, and adult) can be treated according to the present invention. The present invention can also be practiced on animal subjects, particularly mammalian subjects such as mice, rats, dogs, cats, cows, goats, sheep, and horses, for veterinary purposes and for drug screening and drug development purposes. "Subject" is used interchangeably with "individual" and "patient."

[0266] As used herein, "therapy," "therapeutic," "treating," or "treatment" broadly refers to treating a disease, preventing or reducing the progression of a disease or its clinical symptoms, and / or alleviating a disease, causing regression of a disease or its clinical symptoms. Therapy includes prevention, treatment, remedy, reduction, alleviation, and / or providing relief from a disease, signs, and / or symptoms of a disease. Therapy includes alleviating signs and / or symptoms of a disease (e.g., inflammation, pain) in patients with ongoing signs and / or symptoms. Therapy also includes "prevention." The term "reduced" for purposes of therapy broadly refers to a clinically significant reduction in signs and / or symptoms. Therapy includes treatment of recurrent or recurrent signs and / or symptoms (e.g., inflammation, pain). Therapy includes, but is not limited to, preventing the onset of signs and / or symptoms at any time, as well as reducing existing signs and / or symptoms and eliminating existing signs and / or symptoms. Therapy includes treatment of chronic disease ("maintenance") and acute disease. For example, treatment includes treatment or prevention of relapse or recurrence of signs and / or symptoms (e.g., inflammation, pain).

[0267] After defining certain terms and phrases used in this application, the novel glucocorticosteroid agonists, glucocorticosteroid agonist linkers, and ADCs containing same, methods for their production and use, according to the present invention, are further described below.

[0268] The present invention relates to ADCs comprising novel glucocorticosteroid agonists of Formula I, II, or III attached directly or indirectly via a linker to an antibody or antibody fragment comprising an antigen-binding region that binds to an immune cell antigen, typically a human immune cell antigen, such as human V-domain Ig suppressor of T-cell activation (VISTA). However, it is shown herein that ADCs comprising glucocorticosteroid agonists and glucocorticosteroid agonist linkers according to the invention are also effective when conjugated to antibodies or fragments that bind to immune cell antigens other than VISTA.

[0269] In some exemplary embodiments, the ADC comprises an antibody or fragment that possesses a short serum half-life under physiological pH conditions (pH 7.5), for example, the serum half-life of an antibody or fragment in a rodent (human VISTA knock-in) is generally 1-72 hours, 1-32 hours, 1-16 hours, 1-8 hours, 1-4 hours, or 1-2 hours ± 0.5 hours in a human VISTA knock-in rodent, or ≈3.5, 3, 2.5, or 2.3 days ± 0.5 days in a primate (cynomolgus monkey) under physiological pH conditions (pH 7.5); The human VISTA antibody or antibody fragment is attached directly, or indirectly via a linker, to an anti-inflammatory agent, e.g., a steroid or corticosteroid receptor agonist of Formula I, II, or III, or a corticosteroid receptor agonist linker containing the same as disclosed herein, or a functional derivative or radical thereof, i.e., a derivative that, upon administration to a subject, e.g., a human or other mammal, when released from an ADC containing it, induces the desired anti-inflammatory effect upon internalization into immune cells.

[0270] In particular, in the case of ADCs containing anti-VISTA antibodies or antibody fragments, the ADCs specifically bind to VISTA-expressing immune cells at physiological pH, and the corticosteroid receptor agonist of Formula I, II, or III will be released from the ADC upon internalization into target (immune) cells, such as neutrophils, monocytes such as myeloid cells, macrophages, T cells, CD4 T cells, CD8 T cells, Tregs, an...

Claims

1. Glucocorticoid agonist compounds having the following structure of formula (I): 【Chemistry 1】 During the ceremony, X is selected from phenyl, spiro[3.3]heptane, 3-6 membered heterocycle, cycloalkyl, spiroalkyl, spiroheterocycloalkyl, bicyclic alkyl, heterobicyclic alkyl, [1.1.1]bicyclopentane, bicyclo[2.2.2]octane, adamantane, and cubane, each of which can be independently substituted with 1-4 heteroatoms selected from F, Cl, Br, I, N, S, and O, each of whose ring structures can include at least one skeletal heteroatom selected from N, S, and O, and optionally 1-4 C １～３ further substituted with alkyl or C1-3 perfluoroalkyl; Z is selected from phenyl, spiro[3.3]heptane, 3-6 membered heterocycle, cycloalkyl, spiroalkyl, spiroheterocycloalkyl, bicyclic alkyl, heterobicyclic alkyl, [1.1.1]bicyclopentane, bicyclo[2.2.2]octane, adamantane, and cubane, each of which can be independently substituted with 1-4 heteroatoms selected from F, Cl, Br, I, N, S, and O, each of whose ring structures can include at least one skeletal heteroatom selected from N, S, and O, and optionally 1-4 C １～３ further substituted with alkyl or C1-3 perfluoroalkyl; Y is CHR １ , O, S, and N.R. １ is selected from E is CH ２ and O; G is selected from CH and N; Furthermore, when G is CH and X is phenyl, Z is not phenyl; The bond of G to X is optionally C １～３ alkyl and ethylene oxide, each of which may be independently substituted with 1 to 4 heteroatoms selected from N, S, and O, and optionally 1 to 4 C １～３ further substituted with alkyl; The attachment of X to Z may occupy any available position on X and Z; Substituent NR １ R ２ may occupy any available position on Z, R １ is selected from H, linear or branched alkyl groups of 1 to 8 carbons, aryl, and heteroaryl groups, the aryl and heteroaryl groups being alkyl, haloalkyl, halogen, biphenyl, nitro, nitrile, -OH, -O-alkyl, -NH ２ , alkylamino, dialkylamino, thiol, thioalkyl, guanidine, urea, carboxylic acid, alkoxyl, carboxamide, carboxylic acid ester, alkyl-C(O)O-, alkylamino-C(O)-, and dialkylamino-C(O)-; R １ is H, then R ２ may be selected from H, linear or branched alkyl of 1 to 8 carbons, aryl, and heteroaryl groups, said aryl and heteroaryl groups being alkyl, haloalkyl, halogen, biphenyl, nitro, nitrile, -OH, -O-alkyl, -NH ２ , alkylamino, dialkylamino, thiol, thioalkyl, guanidine, urea, carboxylic acid, alkoxyl, carboxamide, carboxylic acid ester, alkyl-C(O)O-, alkylamino-C(O)-, and dialkylamino-C(O)-; R １ is H, a linear or branched alkyl of 1 to 8 carbons, or a heteroaryl; ２ but, [(C=O)CH(W)NH] ｍ -[C=O]-[V] ｋ -J、 C=O)OCH ２ -p-aminophenyl-N-V-J, (C=O)OCH ２ -p-aminophenyl-N-[(C=O)CH(W)NH] ｍ -[C=O]-[V] ｋ -J, and [V] ｋ -(C=O)OCH ２ -p-aminophenyl-N-[(C=O)CH(W)NH] ｍ -[C=O]-J, may be a functional group selected from wherein m=1 to 6, k=0 to 1, and each permutation of W is independently H, n=1 to 4 [(CH ２ ) ｎ R ３ ], R ３ and linear or branched polyethylene oxide groups containing from 1 to 13 units, R ３ is H, methyl, ethyl, isopropyl, OH, O-alkyl, NH ２ , NH-alkyl, N-dialkyl, SH, S-alkyl, guanidine, urea, carboxylic acid, carboxamide, carboxylic ester, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, said aryl and heteroaryl substituents being selected from alkyl, haloalkyl, halogen, biphenyl, nitro, nitrile, -OH, -O-alkyl, -NH ２ , alkylamino, dialkylamino, thiol, thioalkyl, guanidine, urea, carboxylic acid, alkoxyl, carboxamide, carboxylic ester, alkyl-C(O)O-, alkylamino-C(O)-, and dialkylaminoC(O)-; V may be selected from an alkyl chain of 1 to 8 carbons, a linear or branched polyethylene oxide group containing 1 to 13 units, a linear or branched alkyl group containing 1 to 8 carbons, -O-alkyl, a carboxylic acid, a carboxamide, a carboxylic acid ester, alkyl-C(O)O-, alkylamino-C(O)-, dialkylamino-C(O)-, a sequence of 1 to 3 amino acids, each amino acid being independently selected from Glu, Gly, Asn, Asp, Gln, Leu, Lys, Ala, βAla, Phe, Val, and Cit, an aryl, and a heteroaryl group, the aryl and heteroaryl groups being alkyl, haloalkyl, halogen, biphenyl, nitro, nitrile, -OH, -NH ２ , alkylamino, dialkylamino, thiol, thioalkyl, guanidine, urea, carboxylic acid, alkoxyl, carboxamide, carboxylic acid ester, alkyl-C(O)O-, alkylamino-C(O)-, dialkylamino-C(O)-; J is -NH ２ , N ３ , thio, cyclooctyne, -OH, -CO ２ H, transcyclooctene, alkynyl, propargyl, 【Chemistry 2】 is a reactive group selected from In the formula, R ３２ is selected from Cl, Br, F, mesylate, and tosylate; R ３３ is selected from Cl, Br, I, F, OH, —O—N-succinimidyl, —O-(4-nitrophenyl), —O-pentafluorophenyl, or —O-tetrafluorophenyl; R ３４ is H, Me, tetrazine-H, and tetrazine-Me; R ５ But -CH ２ OH, -CH ２ S-H, -C-H ２ Cl, -SCH ２ Cl, -SCH ２ F, -SCH ２ CF ３ , hydroxy, -OCH ２ CN, -OCH ２ Cl, -OCH ２ F, -OCH ３ , -OCH ２ CH ３ , -SCH ２ C.N., and 【Chemistry 3】 is selected from the group consisting of R ６ and R ７ are independently hydrogen and C １～１０ alkyl, Q is H, 【Chemistry 4】 R ８ is a straight or branched alkyl group of 1 to 8 carbons; C(O)R ８ or n=1 to 4, R ４ =H, alkyl or branched alkyl, or P(O)OR ４ (C═O)NR ４ CH ｎ N.R. ４ (C=O)OCH ２ - (V) ｎ -J, A １ and A ２ is independently selected from H and F; Unless otherwise stated, all possible stereoisomers of the glucocorticoid agonist compounds are claimed.

2. X and Z are independently selected from phenyl, spiro[3.3]heptane, [1.1.1]bicyclopentane, and bicyclo[2.2.2]octane; and Y is CH ２ and O, and permutations of W are independently selected from ２ CH ２ CO ２ 2. The glucocorticoid agonist compound of claim 1, wherein Z is selected from H and H, and further wherein when G is CH and X is phenyl, then Z is not phenyl.

3. Glucocorticoid agonist compounds selected from any of the glucocorticoid agonist compounds according to claims 1 or 2, except INX J and INX L, or those disclosed in Example 3.

4. A glucocorticoid agonist compound selected from the INX-steroid payload, INX-steroid linker, and INX-antibody drug conjugate (ADC) compounds disclosed herein, excluding INX J and INX L.

5. below: 【Chemistry 5】 Glucocorticoid agonist compounds selected from:

6. 6. The glucocorticoid agonist compound of any one of claims 1 to 5, which is directly or indirectly attached to at least one cleavable or non-cleavable peptide and / or non-peptide linker (i.e., a "steroid-linker payload" or a "glucocorticosteroid-linker payload").

7. A compound (steroid-linker payload) comprising at least one cleavable or non-cleavable linker ("L"), optionally a "heterobifunctional" or "heterotrifunctional" chemical moiety "Q" used to connect said linker in the compound to an antibody or antibody fragment, and at least one anti-inflammatory agent ("AI"), wherein "AI" has the following structure: Q-L-AI or AI-L-Q The compound (steroid-linker payload) is a glucocorticoid agonist compound according to any one of claims 1 to 6, which can be represented by:

8. The steroid-linker payload of claim 6 or 7, wherein the linker is selected from any of those disclosed herein.

9. PAB and / or amino acids or peptides, optionally 1 to 12 amino acids, further optionally a dipeptide, tripeptide, quattrapeptide, pentapeptide, further optionally Gly, Asn, Asp, Gln, Leu, Lys, Ala, Phe, Cit, Val, Val-Cit, Val-Ala, Val-Gly, Val-Gln, Ala-Val, Cit-Cit, Lys-Val-Cit, Asp-Val-Ala, Ala-Ala-Asn, Asp-V 9. The steroid-linker payload of claim 6, 7 or 8, comprising at least one cleavable or non-cleavable linker selected from al-Ala, Ala-Val-Cit, Ala-Asn-Val, βAla-Leu-Ala-Leu, Lys-Val-Ala, Val-Leu-Lys, Asp-Val-Cit, Val-Ala-Val, and Ala-Ala-Asn, or optionally at least one of GlcA, PAB, and Glu-Gly.

10. A steroid-linker payload comprising at least one glucocorticoid agonist compound according to any one of claims 1 to 6, comprising at least one cleavable linker and / or sacrificial linker attached directly or indirectly to the glucocorticoid agonist steroid compound.

11. 11. The glucocorticoid agonist compound or steroid-linker payload of any one of claims 1 to 10, selected from any of the glucocorticoid agonist compounds or steroid-linker payload compounds disclosed in Example 3, except INX J and INX L.

12. Glucocorticoid agonist (payload) linker conjugates comprising: (i) INX-SM-3-GluGly-alkoxyamine, INX-SM-4-GluGly-alkoxyamine, INX-SM-53-GluGly-alkoxyamine, INX-SM-54-GluGly-alkoxyamine, INX-SM-56-GluGly-alkoxyamine, INX-SM-98-GluGly-alkoxyamine, INX-SM-6-GluGly-alkoxyamine GluGly-alkoxyamine, INX-SM-2-GluGly-alkoxyamine, INX-SM-57-GluGly-alkoxyamine, INX-SM-31-GluGly-alkoxyamine, INX-SM-32-GluGly-alkoxyamine, INX-SM-10-GluGly-alkoxyamine, INX-SM-40-GluGly-alkoxyamine, INX-SM-34-GluGly-alkoxyamine, INX-SM-28-GluGly-alkoxyamine, INX-SM-27-GluGly-alkoxyamine, INX-SM-35-GluGly-alkoxyamine, INX-SM-8-GluGly-alkoxyamine, INX-SM-7-GluGly-alkoxyamine, INX-SM-33-GluGly-alkoxyamine, or a glucocorticoid agonist (payload) linker conjugate in which the Glu-Gly is replaced with a different cleavable peptide linker and / or another INX or INX-SM payload is replaced with an INX-SM payload contained therein, optionally selected from those according to formula I, II, or III, or (ii) INX-SM-53-GluGly-bromoacetyl, INX-SM-3-GluGly-bromoacetyl, INX-SM-54-GluGly-bromoacetyl, INX-SM-1-GluGly-bromoacetyl, INX-SM-4-GluGly-bromoacetyl, INX-SM-2-GluGly-bromoacetyl, INX-SM-47-GluGly-bromoacetyl, INX-SM-7-GluGly-bromoacetyl, INX-SM-8-GluGly-bromoacetyl, INX-SM-56-GluGly-bromoacetyl, INX-SM-32-GluGly-bromoacetyl, INX-SM-6-GluGly-bromoacetyl, INX-SM-10-GluGly-bromoacetyl, INX-SM-33-GluGly-bromoacetyl, INX - Glucocorticoid agonist (payload) linker conjugates, in which Glu-Gly is replaced with a different cleavable peptide linker and / or another INX or INX-SM payload is replaced with an INX-SM payload contained therein, optionally selected from those according to formula I, II or III, (iii) INX-SM-53-GluGly-dibenzocyclooctyne, INX-SM-1-GluGly-dibenzocyclooctyne, INX-SM-4-GluGly-dibenzocyclooctyne, INX-SM-54-GluGly-dibenzocyclooctyne, INX-SM-7-GluGly-dibenzocyclooctyne, INX-SM-8-GluGly-dibenzocyclooctyne, INX-SM-2-GluGly y-Dibenzocyclooctyne, INX-SM-57-GluGly-Dibenzocyclooctyne, INX-SM-40-GluGly-Dibenzocyclooctyne, INX-SM-34-GluGly-Dibenzocyclooctyne, INX-SM-28-GluGly-Dibenzocyclooctyne, INX-SM-27-GluGly-Dibenzocyclooctyne, INX-SM-35-GluGly-Dibenzocyclooctyne, I NX-SM-9-GluGly-dibenzocyclooctyne, INX-SM-10-GluGly-dibenzocyclooctyne, INX-SM-31-GluGly-dibenzocyclooctyne, INX-SM-32-GluGly-dibenzocyclooctyne, INX-SM-33-GluGly-dibenzocyclooctyne, INX-SM-56-GluGly-dibenzocyclooctyne, INX-SM-6-GluGly-dibenzocyclooctyne Glucocorticoid agonist (payload) linker conjugates in which benzocyclooctyne, INX-SM-3-GluGly-dibenzocyclooctyne, or said GluGly is replaced with a different cleavable peptide linker and another INX or INX-SM payload is replaced with an INX-SM payload contained therein, optionally selected from those according to formula I, II, or III; or (iv) INX-SM-1-GluGly-NHS ester, INX-SM-31-GluGly-NHS ester, INX-SM-32-GluGly-NHS ester, INX-SM-33-GluGly-NHS ester, INX-SM-53-GluGly-NHS ester, INX-SM-7-GluGly-NHS ester, INX-SM-8-GluGly-NHS ester, INX -SM-2-GluGly-NHS ester, INX-SM-56-GluGly-NHS ester, INX-SM-6-GluGly-NHS ester, INX-SM-54-GluGly-NHS ester, INX-SM-4-GluGly-NHS ester, INX-SM-53-GluGly-NHS ester, INX-SM-3-GluGly-NHS ester, INX-SM-9-Glu Gly-NHS ester, INX-SM-40-GluGly-NHS ester, INX-SM-34-GluGly-NHS ester, INX-SM-28-GluGly-NHS ester, INX-SM-34-GluGly-NHS ester, INX-SM-28-GluGly-NHS ester, INX-SM-27-GluGly-NHS ester, INX-SM-35-GluGly-NHS ester Glucocorticoid agonist (payload) linker conjugates in which the GluGly is replaced with a different cleavable peptide linker, an INX or an INX-SM payload is replaced with an INX-SM payload contained therein, optionally selected from those according to formula I, II, or III; (v) INX-SM-1-GluGly-maleimide, INX-SM-3-GluGly-maleimide, INX-SM-4-GluGly-maleimide, INX-SM-8-GluGly-maleimide, INX-SM-2-GluGly-maleimide, INX-SM-7-GluGly-maleimide, INX-SM-56-GluGly-maleimide, INX- SM-6-GluGly-maleimide, INX-SM-54-GluGly-maleimide, INX-SM-53-GluGly-maleimide, INX-SM-33-GluGly-maleimide, INX-SM-35-GluGly-maleimide, INX-SM-40-GluGly-maleimide, INX-SM-34-GluGly-maleimide, INX-SM- Glucocorticoid agonist (payload) linker conjugates, in which the GluGly is replaced with a different cleavable peptide linker and another INX or INX-SM payload is replaced with the INX-SM payload contained therein, optionally selected from those according to formula I, II, or III; or (vi) INX-SM-3-GluGly-tetrazine, INX-SM-53-GluGly-tetrazine, INX-SM-1-GluGly-tetrazine, INX-SM-54-GluGly-tetrazine, INX-SM-6-GluGly-tetrazine, INX-SM-56-GluGly-tetrazine, INX-SM-4-GluGly-tetrazine GluGly-tetrazine, INX-SM-10-GluGly-tetrazine, INX-SM-31-GluGly-tetrazine, INX-SM-32-GluGly-tetrazine, INX-SM-33-GluGly-tetrazine, INX-SM-7-GluGly-tetrazine, INX-SM-8-GluGly-tetrazine, INX-SM-9-GluGly-tetrazine GluGly, INX-SM-27-GluGly-tetrazine, INX-SM-35-GluGly-tetrazine, INX-SM-2-GluGly-tetrazine, INX-SM-40-GluGly-tetrazine, INX-SM-34-GluGly-tetrazine, INX-SM-28-GluGly-tetrazine, INX-SM-27-GluGly-tetrazine, or a glucocorticoid agonist (payload) linker conjugate in which the GluGly is replaced with a different cleavable peptide linker and another INX or INX-SM payload is replaced with an INX-SM payload contained therein, optionally selected from those according to formula I, II, or III; or (vii) INX-SM-6-GluGly-amine, INX-SM-54-GluGly-amine, INX-SM-4-GluGly-amine, INX-SM-53-GluGly-amine, INX-SM-2-GluGly-amine, INX-SM-56-GluGly-amine, INX-SM-57-GluGly-amine, INX -SM-35-GluGly-amine, INX-SM-27-GluGly-amine, INX-SM-40-GluGly-amine, INX-SM-34-GluGly-amine, INX-SM-28-GluGly-amine, INX-SM-35-GluGly-amine, INX-SM-9-GluGly-amine, INX-SM-10- or a glucocorticoid agonist (payload) linker conjugate, wherein said GluGly is replaced with a different cleavable peptide linker and another INX or INX-SM payload is replaced with an INX-SM payload contained therein, optionally selected from those according to formula I, II, or III; or (viii) INX-SM-53-PAB-GluGly-alkoxyamine, INX-SM-1-PAB-GluGly-alkoxyamine, INX-SM-3-PAB-GluGly-alkoxyamine, INX-SM-2-PAB-GluGly-alkoxyamine, INX-SM-56-PAB-GluGly-alkoxyamine, INX-SM-35-PAB-GluGly-alkoxyamine, INX-SM-25-PAB-GluGly-alkoxyamine GluGly-alkoxyamine, INX-SM-27-PAB-GluGly-alkoxyamine, INX-SM-35-PAB-GluGly-alkoxyamine, INX-SM-9-PAB-GluGly-alkoxyamine, INX-SM-10-PAB-GluGly-alkoxyamine, INX-SM-31-PAB-GluGly-alkoxyamine, INX-SM-32-PAB-GluGly-alkoxyamine, INX-SM-33-PAB-GluGly-alkoxyamine Thiamine, INX-SM-57-PAB-GluGly-alkoxyamine, INX-SM-7-PAB-GluGly-alkoxyamine, INX-SM-8-PAB-GluGly-alkoxyamine, INX-SM-6-PAB-GluGly-alkoxyamine, INX-SM-54-PAB-GluGly-alkoxyamine, INX-SM-4-PAB-GluGly-alkoxyamine, INX-SM-40-PAB-GluGly-alkoxyamine or another glucocorticoid agonist (payload) linker conjugate, in which the GluGly and / or the PAB are replaced with a different cleavable peptidic or non-peptidic linker and another INX or INX-SM payload is replaced with an INX-SM payload contained therein, optionally selected from those according to formula I, II, or III; or (ix) INX-SM-1-PAB-GluGly-Bromoacetyl, INX-SM-3-PAB-GluGly-Bromoacetyl, INX-SM-2-PAB-GluGly-Bromoacetyl, INX-SM-7-PAB-GluGly-Bromoacetyl, INX-SM-8-PAB-GluGly-Bromoacetyl, INX-SM-40-PAB-GluGly-Bromoacetyl, INX-SM-56-PAB-GluGly -Bromoacetyl, INX-SM-6-PAB-GluGly-Bromoacetyl, INX-SM-154PAB-GluGly-Bromoacetyl, INX-SM-4-PAB-GluGly-Bromoacetyl, INX-SM-33-PAB-GluGly-Bromoacetyl, INX-SM-32-PAB-GluGly-Bromoacetyl, INX-SM-10-PAB-GluGly GluGly-Bromoacetyl, INX-SM-34-PAB-GluGly-Bromoacetyl, INX-SM-31-PAB-GluGly-Bromoacetyl, INX-SM-9-PAB-GluGly-Bromoacetyl, INX-SM-28-PAB-GluGly-Bromoacetyl, INX-SM-27-PAB-GluGly-Bromoacetyl, INX-SM-35-PAB-GluGly-Bromoacetyl, INX-SM-53 -PAB-GluGly-Bromoacetyl or another glucocorticoid agonist (payload) linker conjugate in which the GluGly and / or the PAB are replaced with a different cleavable peptidic or non-peptidic linker and another INX or INX-SM payload is replaced with an INX-SM payload contained therein, optionally selected from those according to formula I, II or III; (x) INX-SM-6-PAB-GluGly-dibenzocyclooctyne, INX-SM-54-PAB-GluGly-dibenzocyclooctyne, INX-SM-4-PAB-GluGly-dibenzocyclooctyne, INX-SM-53-PAB-GluGly-dibenzocyclooctyne, INX-SM-1-PAB-GluGly-dibenzocyclooctyne, INX-SM-7-PAB-GluGly-dibenzocyclooctyne, INX-SM-8-PAB-GluGly -Dibenzocyclooctyne, INX-SM-2-PAB-GluGly-Dibenzocyclooctyne, INX-SM-56-PAB-GluGly-Dibenzocyclooctyne, INX-SM-57-PAB-GluGly-Dibenzocyclooctyne, INX-SM-33-PAB-GluGly-Dibenzocyclooctyne, INX-SM-32-PAB-GluGly-Dibenzocyclooctyne, INX-SM-31-PAB-GluGly-Dibenzocyclooctyne, INX-SM -3-PAB-GluGly-dibenzocyclooctyne, INX-SM-9-PAB-GluGly-dibenzocyclooctyne, INX-SM-27-PAB-GluGly-dibenzocyclooctyne, INX-SM-35-PAB-GluGly-dibenzocyclooctyne, INX-SM-34-PAB-GluGly-dibenzocyclooctyne, INX-SM-28-PAB-GluGly-dibenzocyclooctyne, INX-SM-40-PAB-GluGly-dibenzocyclooctyne cyclooctyne, INX-SM-10-PAB-GluGly-dibenzocyclooctyne, or another glucocorticoid agonist (payload) linker conjugate in which the GluGly and / or the PAB are replaced with a different cleavable peptide or non-peptide linker and another INX or INX-SM payload is replaced with an INX-SM payload contained therein, optionally selected from those according to formula I, II, or III; or (xi) INX-SM-56-PAB-GluGly-NHS ester, INX-SM-54-PAB-GluGly-NHS ester, INX-SM-4-PAB-GluGly-NHS ester, INX-SM-53-PAB-GluGly-NHS ester, INX-SM-1-PAB-GluGly-NHS ester, INX-SM-3-PAB-GluGly-NHS ester, INX-SM-33-PAB -GluGly-NHS ester, INX-SM-57-PAB-GluGly-NHS ester, INX-SM-7-PAB-GluGly-NHS ester, INX-SM-8-PAB-GluGly-NHS ester, INX-SM-27-PAB-GluGly-NHS ester, INX-SM-35-PAB-GluGly-NHS ester, INX-SM-9-PAB-GluGly-NHS ester, IN X-SM-10-PAB-GluGly-NHS ester, INX-SM-31-PAB-GluGly-NHS ester, INX-SM-32-PAB-GluGly-NHS ester, INX-SM-40-PAB-GluGly-NHS ester, INX-SM-34-PAB-GluGly-NHS ester, INX-SM-28-PAB-GluGly-NHS ester, INX-SM-2-PAB-Glu or another glucocorticoid agonist (payload) linker conjugate in which the Gly-NHS ester, or the GluGly and / or the PAB are replaced with a different cleavable peptide or non-peptide linker and another INX or INX-SM payload is replaced with an INX-SM payload contained therein, optionally selected from those according to formula I, II, or III; or (xii) INX-SM-1-PAB-GluGly-maleimide, INX-SM-53-PAB-GluGly-maleimide, INX-SM-5-PAB-GluGly-maleimide, INX-SM-2-PAB-GluGly-maleimide, INX-SM-8-PAB-GluGly-maleimide, INX-SM-56-PAB-GluGly-maleimide, INX-SM-54-PAB-GluGly-maleimide GluGly-maleimide, INX-SM-4-PAB-GluGly-maleimide, INX-SM-57-PAB-GluGly-maleimide, INX-SM-7-PAB-GluGly-maleimide, INX-SM-32-PAB-GluGly-maleimide, INX-SM-31-PAB-GluGly-maleimide, INX-SM-53-PAB-GluGly-maleimide, INX-SM-3-PAB-GluGly- Maleimide, INX-SM-34-PAB-GluGly-maleimide, INX-SM-28-PAB-GluGly-maleimide, INX-SM-40-PAB-GluGly-maleimide, INX-SM-27-PAB-GluGly-maleimide, INX-SM-35-PAB-GluGly-maleimide, INX-SM-9-PAB-GluGly-maleimide, INX-SM-10-PAB-GluG or another glucocorticoid agonist (payload) linker conjugate in which ly-maleimide, or said GluGly and / or said PAB are replaced with a different cleavable peptide or non-peptide linker and another INX or INX-SM payload is replaced with an INX-SM payload contained therein, optionally selected from those according to formula I, II, or III; or (xiii) INX-SM-6-PAB-GluGly-tetrazine, INX-SM-54-PAB-GluGly-tetrazine, INX-SM-4-PAB-GluGly-tetrazine, INX-SM-53-PAB-GluGly-tetrazine, INX-SM-1-PAB-GluGly-tetrazine, INX-SM-3-PAB-GluGly-tetrazine, INX-SM-57-PAB-GluGly-tetrazine, I NX-SM-7-PAB-GluGly-tetrazine, INX-SM-8-PAB-GluGly-tetrazine, INX-SM-2-PAB-GluGly-tetrazine, INX-SM-31-PAB-GluGly-tetrazine, INX-SM-32-PAB-GluGly-tetrazine, INX-SM-33-PAB-GluGly-tetrazine, INX-SM-56-PAB-GluGly-tetrazine, INX-SM- 35-PAB-GluGly-tetrazine, INX-SM-9-PAB-GluGly-tetrazine, INX-SM-40-PAB-GluGly-tetrazine, INX-SM-34-PAB-GluGly-tetrazine, INX-SM-28-PAB-GluGly-tetrazine, INX-SM-27-PAB-GluGly-tetrazine, INX-SM-35-PAB-GluGly-tetrazine, INX-SM-10-P or another glucocorticoid agonist (payload) linker conjugate in which AB-GluGly-tetrazine or said GluGly and / or said PAB are replaced with a different cleavable peptide or non-peptide linker and another INX or INX-SM payload is replaced with an INX-SM payload contained therein, optionally selected from those according to formula I, II, or III; or (xiv) INX-SM-1-PAB-GluGly-amine, INX-SM-3-PAB-GluGly-amine, INX-SM-8-PAB-GluGly-amine, INX-SM-2-PAB-GluGly-amine, INX-SM-56-PAB-GluGly-amine, INX-SM-6-PAB-GluGly-, or an amine according to formula I, II, or III, INX-SM-54-PAB-GluGly-amine, GluGly-amine, INX-SM-4-PAB-GluGly-amine, INX-SM-53-PAB-GluGly-amine, INX-SM-33-PAB-GluGly-amine, INX-SM-53-PAB-GluGly-amine, INX-SM-7-PAB-GluGly-amine, INX-SM-9-PAB-GluGly-amine, INX-SM-35-PAB-GluGly-amine, INX-S M-40-PAB-GluGly-amine, INX-SM-34-PAB-GluGly-amine, INX-SM-28-PAB-GluGly-amine, INX-SM-27-PAB-GluGly-amine, INX-SM-35-PAB-GluGly-amine, INX-SM-10-PAB-GluGly-amine, INX-SM-31-PAB-GluGly-amine, INX-SM-32-PAB-GluGly-amine or another glucocorticoid agonist (payload) linker conjugate in which uGly-amine, or said GluGly and / or said PAB are replaced with a different cleavable peptide or non-peptide linker and another INX or INX-SM payload is replaced with an INX-SM payload contained therein, optionally selected from those according to formula I, II, or III; or (xv) INX-SM-1-PAB-GlcA-alkoxyamine, INX-SM-35-PAB-GlcA-alkoxyamine, INX-SM-9-PAB-GlcA-alkoxyamine, INX-SM-10-PAB-GlcA-alkoxyamine, INX-SM-54-PAB-GlcA-alkoxyamine, INX-SM-31-PAB-GlcA-alkoxyamine, INX-SM-32-PAB-GlcA-alkoxyamine koxyamine, INX-SM-33-PAB-GlcA-alkoxyamine, INX-SM-57-PAB-GlcA-alkoxyamine, INX-SM-7-PAB-GlcA-alkoxyamine, INX-SM-8-PAB-GlcA-alkoxyamine, INX-SM-2-PAB-GlcA-alkoxyamine, INX-SM-56-PAB-GlcA-alkoxyamine, INX-SM-6-PAB-GlcA-alkoxyamine or another glucocorticoid agonist (payload) linker conjugate, wherein the GlcA and / or the PAB are replaced with a different cleavable peptide or non-peptide linker, and / or another INX or INX-SM payload is replaced with an INX-SM payload contained therein, optionally selected from those according to formula I, II, or III, or (xvi) INX-SM-3-PAB-GlcA-bromoacetyl, INX-SM-4-PAB-GlcA-bromoacetyl, INX-SM-56-PAB-GlcA-bromoacetyl, INX-SM-54-PAB-GlcA-bromoacetyl, INX-SM-4-PAB-GlcA-bromoacetyl, INX-SM-53-PAB-GlcA-bromoacetyl, INX-SM-7-PAB-GlcA-bromoacetyl Cetyl, INX-SM-8-PAB-GlcA-bromoacetyl, INX-SM-2-PAB-GlcA-bromoacetyl, INX-SM-40-PAB-GlcA-bromoacetyl, INX-SM-57-PAB-GlcA-bromoacetyl, INX-SM-33-PAB-GlcA-bromoacetyl, INX-SM-10-PAB-GlcA-bromoacetyl, INX-SM-34-PAB-GlcA-bromoacetyl cetyl, INX-SM-31-PAB-GlcA-bromoacetyl, INX-SM-32-PAB-GlcA-bromoacetyl, INX-SM-35-PAB-GlcA-bromoacetyl, INX-SM-9-PAB-GlcA-bromoacetyl, INX-SM-28-PAB-GlcA-bromoacetyl, INX-SM-27-PAB-GlcA-bromoacetyl, INX-SM-1-PAB-GlcA-bromoacetyl, or another glucocorticoid agonist (payload) linker conjugate in which the GluGly and / or the PAB are replaced with a different cleavable peptide or non-peptide linker and / or another INX or INX-SM payload is replaced with an INX-SM payload contained therein, optionally selected from those according to formula I, II, or III, or (xvii) INX-SM-4-PAB-GlcA-dibenzocyclooctyne, INX-SM-54-PAB-GlcA-dibenzocyclooctyne, INX-SM-1-PAB-GlcA-dibenzocyclooctyne, INX-SM-54-PAB-GlcA-dibenzocyclooctyne, INX-SM-33-PAB-GlcA-dibenzocyclooctyne, INX-SM-57-PAB-GlcA-dibenzocyclooctyne, INX-SM-7-PAB-GlcA-dibenzocyclo octyne, INX-SM-8-PAB-GlcA-dibenzocyclooctyne, INX-SM-2-PAB-GlcA-dibenzocyclooctyne, INX-SM-5-PAB-GlcA-dibenzocyclooctyne, INX-SM-6-PAB-GlcA-dibenzocyclooctyne, INX-SM-35-PAB-GlcA-dibenzocyclooctyne, INX-SM-9-PAB-GlcA-dibenzocyclooctyne, INX-SM-10-PAB-GlcA-dibenzocyclooctyne INX-SM-31-PAB-GlcA-dibenzocyclooctyne, INX-SM-32-PAB-GlcA-dibenzocyclooctyne, INX-SM-27-PAB-GlcA-dibenzocyclooctyne, INX-SM-35-PAB-GlcA-dibenzocyclooctyne, INX-SM-28-PAB-GlcA-dibenzocyclooctyne, INX-SM-34-PAB-GlcA-dibenzocyclooctyne, INX-SM-40-PAB-GlcA-dibenzocyclooctyne or another glucocorticoid agonist (payload) linker conjugate, in which the GlcA and / or the PAB are replaced with a different cleavable peptide or non-peptide linker, and / or another INX or INX-SM payload is replaced with an INX-SM payload contained therein, optionally selected from those according to formula I, II, or III; or (xviii) INX-SM-3-PAB-GlcA-NHS ester, INX-SM-53-PAB-GlcA-NHS ester, INX-SM-4-PAB-GlcA-NHS ester, INX-SM-56-PAB-GlcA-NHS ester, INX-SM-54-PAB-GlcA-NHS ester, INX-SM-8-PAB-GlcA-NHS ester, INX-SM-2-PAB-G INX-SM-7-PAB-GlcA-NHS ester, INX-SM-57-PAB-GlcA-NHS ester, INX-SM-32-PAB-GlcA-NHS ester, INX-SM-33-PAB-GlcA-NHS ester, INX-SM-31-PAB-GlcA-NHS ester, INX-SM-9-PAB-GlcA-NHS ester, INX-SM-1 0-PAB-GlcA-NHS ester, INX-SM-35-PAB-GlcA-NHS ester, INX-SM-27-PAB-GlcA-NHS ester, INX-SM-28-PAB-GlcA-NHS ester, INX-SM-40-PAB-GlcA-NHS ester, INX-SM-34-PAB-GlcA-NHS ester, INX-SM-1-PAB-GlcA-NHS ester, or another glucocorticoid agonist (payload) linker conjugate, in which the GlcA and / or the PAB are replaced with a different cleavable peptide or non-peptide linker, and / or another INX or INX-SM payload is replaced with an INX-SM payload contained therein, optionally selected from those according to formula I, II, or III, or (xix) INX-SM-3-PAB-GlcA-maleimide, INX-SM-4-PAB-GlcA-maleimide, INX-SM-53-PAB-GlcA-maleimide, INX-SM-31-PAB-GlcA-maleimide, INX-SM-32-PAB-GlcA-maleimide, INX-SM-33-PAB-GlcA-maleimide, INX-SM-53-PAB-GlcA-maleimide amide, INX-SM-7-PAB-GlcA-maleimide, INX-SM-8-PAB-GlcA-maleimide, INX-SM-2-PAB-GlcA-maleimide, INX-SM-56-PAB-GlcA-maleimide, INX-SM-6-PAB-GlcA-maleimide, INX-SM-54-PAB-GlcA-maleimide, INX-SM-1-PAB-GlcA-maleimide, INX - SM-9-PAB-GlcA-maleimide, INX-SM-35-PAB-GlcA-maleimide, INX-SM-27-PAB-GlcA-maleimide, INX-SM-28-PAB-GlcA-maleimide, INX-SM-34-PAB-GlcA-maleimide, INX-SM-40-PAB-GlcA-maleimide, INX-SM-10-PAB-GlcA-maleimide, or another glucocorticoid agonist (payload) linker conjugate, in which the GlcA and / or the PAB are replaced with a different cleavable peptide or non-peptide linker, and / or another INX or INX-SM payload is replaced with an INX-SM payload contained therein, optionally selected from those according to formula I, II, or III, or (xx) INX-SM-33-PAB-GlcA-tetrazine, INX-SM-57-PAB-GlcA-tetrazine, INX-SM-7-PAB-GlcA-tetrazine, INX-SM-8-PAB-GlcA-tetrazine, INX-SM-2-PAB-GlcA-tetrazine, INX-SM-56-PAB-GlcA-tetrazine, INX-SM-6-PAB-GlcA-tetrazine, INX-SM-54-PAB-GlcA-tetrazine, INX-SM-4-PAB-GlcA-tetrazine, INX-SM-9-PAB-GlcA-tetrazine, INX-SM-35-PAB-GlcA-tetrazine, INX-SM-27-PAB-GlcA-tetrazine or another glucocorticoid agonist (payload) linker conjugate, wherein said GlcAy and / or said PAB are replaced with a different cleavable peptide or non-peptide linker, and / or another INX or INX-SM payload is replaced with an INX-SM payload contained therein, optionally selected from those according to formula I, II, or III; or (xxi) INX-SM-1-PAB-GlcA-amine, INX-SM-3-PAB-GlcA-amine, INX-SM-53-PAB-GlcA-amine, INX-SM-6-PAB-GlcA-amine, INX-SM-54-PAB-GlcA-amine, INX-SM-8-PAB-GlcA-amine, INX-SM-2-PAB-GlcA-amine, INX-SM-56- PAB-GlcA-amine, INX-SM-4-PAB-GlcA-amine, INX-SM-35-PAB-GlcA-amine, INX-SM-8-PAB-GlcA-amine, INX-SM-10-PAB-GlcA-amine, INX-SM-31-PAB-GlcA-amine, INX-SM-32-PAB-GlcA-amine, INX-SM-33-PAB-GlcA-amine , INX-SM-57-PAB-GlcA-amine, INX-SM-27-PAB-GlcA-amine, INX-SM-35-PAB-GlcA-amine, INX-SM-34-PAB-GlcA-amine, INX-SM-28-PAB-GlcA-amine, INX-SM-40-PAB-GlcA-amine, INX-SM-7-PAB-GlcA-amine, or another glucocorticoid agonist (payload) linker conjugate, in which the GlcA and / or the PAB are replaced with a different cleavable peptide or non-peptide linker, and / or another INX or INX-SM payload is replaced with an INX-SM payload contained therein, optionally selected from those according to formula I, II, or III, or (xxii) other INX linker payloads, in which alkoxyamine-GlcA-PAB-DMEDA-INX-SM3, or alkoxyamine-GlyGlu-PAB-DMEDA-INX-SM3, or INX-SM3 is replaced by another compound of formula I, II, or III and comprises the same or a different peptide or non-peptide linker, said linker being attached to the same or a different INX steroid via C11-OH, (xxiii) other INX linker payloads, in which Bromoacetyl-GlcA-PAB-DMEDA-INX-SM3, or Bromoacetyl-GlyGlu-PAB-DMEDA-INX-SM3, or INX-SM3 is replaced by another compound of formula I, II, or III, and / or comprises the same or a different peptide or non-peptide linker, said linker being attached to the same or a different INX steroid via C11-OH, (xxiv) other INX linker payloads in which dibenzocyclooctyne-GlcA-PAB-DMEDA-INX-SM3, or dibenzocyclooctyne-GlyGlu-PAB-DMEDA-INX-SM3, or INX-SM3 is replaced by another compound of formula I, II or III and / or comprises the same or a different peptidic or non-peptidic linker, said linker being attached to the same or a different INX steroid via C11-OH, (xxv) other INX linker payloads, in which tetrazine-GlcA-PAB-DMEDA-INX-SM3, or tetrazine-GlyGlu-PAB-DMEDA-INX-SM3, or INX-SM3, is replaced by another compound of formula I, II or III and / or comprises the same or a different peptide or non-peptide linker, said linker being attached to the same or a different INX steroid via C11-OH, (xxvi) other INX linker payloads, in which alkoxyamine-GlcA-PAB-DMEDA-INX-SM3, or alkoxyamine-GlyGlu-PAB-DMEDA-INX-SM3, or INX-SM3 is replaced by another compound of formula I, II, or III and / or comprises the same or a different linker, the linker being attached via C17 to the same or a different INX steroid payload, (xxvii) Bromoacetyl-GlcA-PAB-DMEDA-INX-SM3, or Bromoacetyl-GlyGlu-PAB-DMEDA-INX-SM3, or other INX linker payloads in which INX-SM3 is replaced by another compound of formula I, II, or III, and / or includes the same or a different INX steroid payload via C17; (xxviii) other INX linker payloads, in which Maleimido-GlcA-PAB-DMEDA-INX-SM3, or Maleimido-GlyGlu-PAB-DMEDA-INX-SM3, or INX-SM3 is replaced by another compound of formula I, II or III and / or comprises the same or a different linker, said linker being attached via C17 to the same or a different INX steroid payload, (xxix) other INX linker payloads, in which Dibenzocyclooctyne-GlcA-PAB-DMEDA-INX-SM3, or Dibenzocyclooctyne-GlyGlu-PAB-DMEDA-INX-SM3, or INX-SM3 is replaced by another compound of formula I, II, or III and / or comprises the same or a different linker, said linker being attached via C17 to the same or a different INX steroid payload, (xxx) tetrazine-GlcA-PAB-DMEDA-INX-SM3, or tetrazine-GlyGlu-PAB-DMEDA-INX-SM3, or other INX linker payloads in which INX-SM3 is replaced by another compound of formula I, II, or III, and / or includes the same or a different INX steroid payload via C17; (xxxi) The glucocorticoid agonist (payload) linker conjugates selected from amine-GlcA-PAB-DMEDA-INX-SM3, or amine-GlyGlu-PAB-DMEDA-INX-SM3, or other INX linker payloads, where INX-SM3 is replaced by another compound of formula I, II, or III and includes the same or a different INX steroid payload via C17.

13. An antibody drug conjugate (ADC) comprising: (i) Ab-Gly-Glu-PAB-DMEDA-INX-3 or Ab-GlcA-PAB-DMEDA-INX-SM-3 (alkoxyamine + ketone conjugation (C11-OH linkage), or another ADC comprising a different INX-SM payload, where INX-SM3 is replaced with another compound of formula I, II, or III and the other INX-SM payload is conjugated to the antibody via alkoxyamine + ketone conjugation and C11-OH linked; (ii) Ab-Gly-Glu-PAB-DMEDA-INX-3 or Ab-GlcA-PAB-DMEDA-INX-SM-3 (azide + dibenzocyclooctyne conjugation (C11-OH linkage), or another ADC comprising a different INX-SM payload, where INX-SM3 is replaced with another compound of formula I, II, or III and the INX-SM payload is conjugated to the antibody via azide + dibenzocyclooctyne conjugation and C11-OH linked; (iii) another ADC comprising a different INX-SM payload, where Ab-Gly-Glu-PAB-DMEDA-INX-3 or Ab-GlcA-PAB-DMEDA-INX-SM-3 (haloacetyl + cysteine ​​conjugation (C11-OH linkage), or INX-SM3 is replaced with another compound of formula I, II, or III and conjugated to the antibody via azide + dibenzocyclooctyne conjugation and C11-OH linkage; (iv) another ADC comprising a different INX-SM payload, where Ab-Gly-Glu-PAB-DMEDA-INX-3 or Ab-GlcA-PAB-DMEDA-INX-SM-3 (maleimide + cysteine ​​conjugation (C11-OH linkage), or INX-SM3 is replaced with another compound of formula I, II, or III and conjugated to the antibody via azide + dibenzocyclooctyne conjugation and C11-OH linked; (v) Ab-Gly-Glu-PAB-DMEDA-INX-3 or Ab-GlcA-PAB-DMEDA-INX-SM-3 (tetrazine + trans cyclooctene conjugation (C11-OH linkage), or another ADC comprising a different INX-SM payload, where INX-SM3 is replaced with another compound of formula I, II, or III and conjugated to the antibody via tetrazine + trans cyclooctene conjugation and C11-OH linked; (vi) another ADC comprising a different INX-SM payload, where Ab-Gly-Glu-PAB-DMEDA-INX-3 or Ab-GlcA-PAB-DMEDA-INX-SM-3 (alkoxyamine + ketone conjugation (C11-OH linkage)), or INX-SM3 is replaced with another compound of formula I, II, or III and conjugated to the antibody via alkoxyamine + ketone conjugation and C11-OH linked; (vii) another ADC comprising a different INX-SM payload, where Ab-Gly-Glu-PAB-DMEDA-INX-3 or Ab-GlcA-PAB-DMEDA-INX-SM-3 (azide + dibenzocyclooctyne conjugation (C17 linkage)), or INX-SM3 is replaced with another compound of formula I, II, or III and is conjugated to the antibody via azide + dibenzocyclooctyne conjugation and C17 linked; (viii) another ADC comprising a different INX-SM payload, where Ab-Gly-Glu-PAB-DMEDA-INX-3 or Ab-GlcA-PAB-DMEDA-INX-SM-3 (haloacetyl + cysteine ​​conjugation (C17 linkage)), or INX-SM3 is replaced with another compound of formula I, II, or III and conjugated to the antibody via azide + dibenzocyclooctyne conjugation and C17 linked; (ix) Ab-Gly-Glu-PAB-DMEDA-INX-3 or Ab-GlcA-PAB-DMEDA-INX-SM-3 (tetrazine + transcyclooctene conjugation (C17 linkage)), or another ADC comprising a different INX-SM payload, wherein the INX-SM linker payload is conjugated to the antibody via a tetrazine + transcyclooctene conjugation and C17 linked; (x) Ab-Gly-Glu-PAB-DMEDA-INX-3 or Ab-GlcA-PAB-DMEDA-INX-SM-3 (amine + glutamine conjugation using transglutaminase (C17 linkage)), or another ADC comprising a different INX-SM payload, where the INX-SM linker payload is conjugated to the antibody via amine + glutamine conjugation using transglutaminase and C17 linked; (xi) INX-SM-3-PAB-GlcA-Ab or INX-SM-3-PAB-Glu-Gly-Ab (alkoxyamine and ketone conjugation) (N-linked payload), or another ADC comprising a different INX-SM payload, in which INX-SM3 is replaced with another compound of formula I, II, or III payload and is conjugated to the antibody via alkoxyamine and ketone conjugation and N-linked; (xii) INX-SM-3-PAB-GlcA-Ab or INX-SM-3-PAB-Glu-Gly-Ab (haloacetyl conjugation) (N-linked payload), or another ADC comprising a different INX-SM payload, in which INX-SM3 is replaced with another compound of formula I, II, or III payload and is conjugated to the antibody via a haloacetyl conjugation and N-linked; (xiii) INX-SM-3-PAB-GlcA-Ab or INX-SM-3-PAB-Glu-Gly-Ab (azide + dibenzocyclooctyne conjugation) (N-linked payload), or another ADC comprising a different INX-SM payload, in which INX-SM3 is replaced with another compound of formula I, II, or III payload and is conjugated to the antibody via azide + dibenzocyclooctyne conjugation and N-linked; (xiv) INX-SM-3-GlcA-Ab or INX-SM-3-Glu-Gly-Ab (N-hydroxysuccinimide conjugation) (N-linked payload), or another ADC comprising a different INX-SM payload, in which INX-SM3 is replaced with another compound of formula I, II, or III payload and is conjugated and N-linked to the antibody via N-hydroxysuccinimide conjugation; (xv) INX-SM-3-PAB-GlcA-Ab or INX-SM-3-PAB-Glu-Gly-Ab (azide + dibenzocyclooctyne conjugation) (N-linked payload), or another ADC comprising a different INX-SM payload, in which INX-SM3 is replaced with another compound of formula I, II, or III payload and is conjugated to the antibody via azide + dibenzocyclooctyne conjugation and N-linked; (xvi) INX-SM-3-PAB-GlcA-Ab or INX-SM-3-PAB-Glu-Gly-Ab (N-hydroxysuccinimide conjugation) (N-linked payload), or another ADC comprising a different INX-SM payload, in which INX-SM3 is replaced with another compound of formula I, II, or III payload and is conjugated and N-linked to the antibody via N-hydroxysuccinimide conjugation; (xvii) INX-SM-3-Glu-Gly-Ab or INX-SM-3-PAB-Glu-Gly-Ab (maleimide conjugation) (N-linked payload), or another ADC comprising a different INX-SM payload, in which INX-SM3 is replaced with another compound of formula I, II, or III payload and is conjugated to the antibody via maleimide conjugation and N-linked; (xviii) INX-SM-3-Glu-Gly-Ab or INX-SM-3-PAB-Glu-Gly-Ab or INX-SM-3-PAB-GlcA-Ab (transcyclooctene + tetrazine conjugation) (N-linked payload), or another ADC comprising a different INX-SM payload, in which INX-SM3 is replaced with another compound of formula I, II, or III payload and is conjugated to the antibody via a transcyclooctene + tetrazine conjugation and is N-linked; (xix) the antibody drug conjugate (ADC) selected from INX-SM-3-Glu-Gly-Ab or INX-SM-3-PAB-Glu-Gly-Ab or INX-SM-3-PAB-GlcA-Ab (amine conjugation) (N-linked payload), or another ADC comprising a different INX-SM payload, where INX-SM3 is replaced with another compound of formula I, II, or III payload and is conjugated to the antibody via a transcyclooctene + tetrazine conjugation and N-linked.

14. An antibody drug conjugate (ADC) selected from: 【Chemistry 6】 During the ceremony, Ab = antibody, preferably an antibody that binds to human immune cells, preferably an anti-VISTA antibody that binds to human VISTA immune cells at physiological pH; L = linker, AA = single, double, or triple amino acid sequence; NH Payload = 【Chemistry 7】 R ＥＧ are independently hydrogen, alkyl, biphenyl, -CF ３ , -NO ２ , —CN, fluoro, bromo, chloro, alkoxyl, alkylamino, dialkylamino, alkyl-C(O)O—, alkylamino-C(O)—, and dialkylaminoC(O)—; 【Chemistry 8】 Ab=antibody, L = linker, AA = single, double, or triple amino acid sequence; NH Payload = 【Chemistry 9】 R ＥＧ are independently hydrogen, alkyl, biphenyl, -CF ３ , -NO ２ , —CN, fluoro, bromo, chloro, alkoxyl, alkylamino, dialkylamino, alkyl-C(O)O—, alkylamino-C(O)—, and dialkylaminoC(O)—; 【Chemistry 10】 Ab=antibody, L = linker, AA = single, double, or triple amino acid sequence, or absent; NH Payload = 【Chemistry 11】 R ＥＧ are independently hydrogen, alkyl, biphenyl, -CF ３ , -NO ２ , —CN, fluoro, bromo, chloro, alkoxyl, alkylamino, dialkylamino, alkyl-C(O)O—, alkylamino-C(O)—, and dialkylaminoC(O)—; RT=AA or 【Chemistry 12】 【Chemistry 13】 Ab = antibody, optionally an anti-human VISTA antibody; L = linker, AA = single, double, or triple amino acid sequence; O Payload = 【Chemistry 14】 【Chemistry 15】 Ab=antibody, L = linker, AA = single, double, or triple amino acid sequence, or absent; O Payload = 【Chemistry 16】 RT=AA or 【Chemistry 17】 The antibody drug conjugate (ADC),

15. The antibody drug conjugate (ADC) of claim 14 , wherein the linker comprises a cleavable or non-cleavable peptide or a sacrificial linker.

16. PAB and / or amino acids or peptides, optionally 1-12 amino acids, further optionally a dipeptide, tripeptide, quattrapeptide, pentapeptide, further optionally Gly, Asn, Asp, Gln, Leu, Lys, Ala, Phe, Cit, Val, Val-Cit, Val-Ala, Val-Gly, Val-Gln, Ala-Val, Cit-Cit, Lys-Val-Cit, 16. The antibody drug conjugate (ADC) of any one of claims 13 to 15, comprising a linker selected from Asp-Val-Ala, Ala-Ala-Asn, Asp-Val-Ala, Ala-Val-Cit, Ala-Asn-Val, βAla-LeuAla-Leu, Lys-Val-Ala, Val-Leu-Lys, Asp-Val-Cit, Val-Ala-Val, and Ala-Ala-Asn.

17. A steroid-antibody conjugate selected from the following structures: 【Chemistry 18】 wherein n=2-12, 2-10, 2-8, 2-6, 2-4, and A is an antibody or antigen-binding fragment thereof, preferably an antibody or antibody fragment that binds to an antigen expressed on an immune cell, preferably a human immune cell, more preferably an anti-human VISTA antibody.

18. Glucocorticoid agonist compounds of formula (I): 【Chemistry 19】 During the ceremony, X is selected from phenyl, spiro[3.3]heptane, 3-6 membered heterocycle, cycloalkyl, spiroalkyl, spiroheterocycloalkyl, bicyclic alkyl, heterobicyclic alkyl, [1.1.1]bicyclopentane, bicyclo[2.2.2]octane, adamantane, and cubane, each of which can be independently substituted with 1-4 heteroatoms selected from F, Cl, Br, I, N, S, and O, each of whose ring structures can include at least one skeletal heteroatom selected from N, S, and O, and optionally 1-4 C １～３ further substituted with alkyl or C1-3 perfluoroalkyl; Z is selected from phenyl, spiro[3.3]heptane, 3-6 membered heterocycle, cycloalkyl, spiroalkyl, spiroheterocycloalkyl, bicyclic alkyl, heterobicyclic alkyl, [1.1.1]bicyclopentane, bicyclo[2.2.2]octane, adamantane, and cubane, each of which can be independently substituted with 1-4 heteroatoms selected from F, Cl, Br, I, N, S, and O, each of whose ring structures can include at least one skeletal heteroatom selected from N, S, and O, and optionally 1-4 C １～３ further substituted with alkyl or C1-3 perfluoroalkyl; Y is CHR １ , O, S, and N.R. １ is selected from E is CH ２ and O; G is selected from CH and N; Furthermore, when G is CH and X is phenyl, Z is not phenyl; The bond of G to X is optionally C １～３ alkyl and ethylene oxide, each of which may be independently substituted with 1 to 4 heteroatoms selected from N, S, and O, and optionally 1 to 4 C １～３ further substituted with alkyl; The attachment of X to Z may occupy any available position on X and Z; Substituent NR １ R ２ may occupy any available position on Z, R １ is selected from H, linear or branched alkyl groups of 1 to 8 carbons, aryl, and heteroaryl groups, the aryl and heteroaryl groups being alkyl, haloalkyl, halogen, biphenyl, nitro, nitrile, -OH, -O-alkyl, -NH ２ , alkylamino, dialkylamino, thiol, thioalkyl, guanidine, urea, carboxylic acid, alkoxyl, carboxamide, carboxylic acid ester, alkyl-C(O)O-, alkylamino-C(O)-, and dialkylamino-C(O)-; R １ is H, then R ２ may be selected from H, linear or branched alkyl of 1 to 8 carbons, aryl, and heteroaryl groups, said aryl and heteroaryl groups being alkyl, haloalkyl, halogen, biphenyl, nitro, nitrile, -OH, -O-alkyl, -NH ２ , alkylamino, dialkylamino, thiol, thioalkyl, guanidine, urea, carboxylic acid, alkoxyl, carboxamide, carboxylic acid ester, alkyl-C(O)O-, alkylamino-C(O)-, and dialkylamino-C(O)-; R １ is H, a linear or branched alkyl of 1 to 8 carbons, or a heteroaryl; ２ but, [(C=O)CH(W)NH] ｍ -[C=O]-[V] ｋ -J、 C=O)OCH ２ -p-aminophenyl-N-V-J, (C=O)OCH ２ -p-aminophenyl-N-[(C=O)CH(W)NH] ｍ -[C=O]-[V] ｋ -J, and [V] ｋ -(C=O)OCH ２ -p-aminophenyl-N-[(C=O)CH(W)NH] ｍ -[C=O]-J, may be a functional group selected from wherein m=1 to 6, k=0 to 1, and each permutation of W is independently H, n=1 to 4 [(CH ２ ) ｎ R ３ ], R ３ and linear or branched polyethylene oxide groups containing from 1 to 13 units, R ３ is H, methyl, ethyl, isopropyl, OH, O-alkyl, NH ２ , NH-alkyl, N-dialkyl, SH, S-alkyl, guanidine, urea, carboxylic acid, carboxamide, carboxylic ester, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, said aryl and heteroaryl substituents being selected from alkyl, haloalkyl, halogen, biphenyl, nitro, nitrile, -OH, -O-alkyl, -NH ２ , alkylamino, dialkylamino, thiol, thioalkyl, guanidine, urea, carboxylic acid, alkoxyl, carboxamide, carboxylic ester, alkyl-C(O)O-, alkylamino-C(O)-, and dialkylaminoC(O)-; V may be selected from an alkyl chain of 1 to 8 carbons, a linear or branched polyethylene oxide group containing 1 to 13 units, a linear or branched alkyl group containing 1 to 8 carbons, -O-alkyl, a carboxylic acid, a carboxamide, a carboxylic acid ester, alkyl-C(O)O-, alkylamino-C(O)-, dialkylamino-C(O)-, a sequence of 1 to 3 amino acids, each amino acid being independently selected from Glu, Gly, Asn, Asp, Gln, Leu, Lys, Ala, βAla, Phe, Val, and Cit, an aryl, and a heteroaryl group, the aryl and heteroaryl groups being alkyl, haloalkyl, halogen, biphenyl, nitro, nitrile, -OH, -NH ２ , alkylamino, dialkylamino, thiol, thioalkyl, guanidine, urea, carboxylic acid, alkoxyl, carboxamide, carboxylic acid ester, alkyl-C(O)O-, alkylamino-C(O)-, dialkylamino-C(O)-; J is -NH ２ , N ３ , thio, cyclooctyne, -OH, -CO ２ H, transcyclooctene, alkynyl, propargyl, 【Chemistry 20】 is a reactive group selected from In the formula, R ３２ is selected from Cl, Br, F, mesylate, and tosylate; R ３３ is selected from Cl, Br, I, F, OH, —O—N-succinimidyl, —O-(4-nitrophenyl), —O-pentafluorophenyl, or —O-tetrafluorophenyl; R ３４ is H, Me, tetrazine-H, and tetrazine-Me; R ５ But -CH ２ OH, -CH ２ S-H, -C-H ２ Cl, -SCH ２ Cl, -SCH ２ F, -SCH ２ CF ３ , hydroxy, -OCH ２ CN, -OCH ２ Cl, -OCH ２ F, -OCH ３ , -OCH ２ CH ３ , -SCH ２ C.N., and 【Chemistry 21】 is selected from the group consisting of R ６ and R ７ are independently hydrogen and C １～１０ alkyl, Q is H, 【Chemical 22】 R ８ is a straight or branched alkyl group of 1 to 8 carbons; C(O)R ８ or n=1 to 4, R ４ =H, alkyl or branched alkyl, or P(O)OR ４ (C═O)NR ４ CH ｎ N.R. ４ (C=O)OCH ２ - (V) ｎ -J, A １ and A ２ is independently selected from H and F; Unless otherwise stated, all possible stereoisomers of the glucocorticoid agonist compounds are claimed.

19. Z, 【Chemistry 23】 each of which may be independently substituted with 1 to 4 heteroatoms selected from F, Cl, Br, I, N, S, and O; and optionally 1 to 4 C １～３ Alkyl or C １～３ further substituted with a perfluoroalkyl group; Each of the ring structures may contain at least one additional skeletal heteroatom selected from N, S, and O; During the ceremony, each 【Chemistry 24】 20. The compound of claim 18, wherein: represents a point of attachment to the remainder of the formula, each of which may be covalently bonded to the remainder of the formula through an additional heteroatom selected from N, S, and O.

20. Z-NR １ but, 【Chemistry 25】 is selected from Each of these may be independently substituted with 1 to 4 heteroatoms selected from F, Cl, Br, I, N, S, and O, and optionally 1 to 4 C １～３ Alkyl or C １～３ further substituted with a perfluoroalkyl group; Each of the ring structures may contain at least one additional skeletal heteroatom selected from N, S, and O; During the ceremony, each 【Chemistry 26】 represents a point of attachment to the remainder of the formula, each of which may be covalently bonded to the remainder of the formula via an additional heteroatom selected from N, S, and O.

21. Possessing the structure of formula (II): 【Chemistry 27】 During the ceremony, Y is CH ２ and O; E is CH ２ and O; G is selected from CH and N; L is selected from H and F; R ５ But -CH ２ OH, -SCH ２ F, and 【Chemistry 28】 is selected from A １ and A ２ is independently selected from H and F; V may be selected from an alkyl chain of 1 to 8 carbons, a linear or branched polyethylene oxide group containing 1 to 13 units, a linear or branched alkyl group containing 1 to 8 carbons, -O-alkyl, a carboxylic acid, a carboxamide, a carboxylic acid ester, alkyl-C(O)O-, alkylamino-C(O)-, dialkylamino-C(O)-, a sequence of 1 to 3 amino acids, each amino acid being independently selected from Glu, Gly, Asn, Asp, Gln, Leu, Lys, Ala, βAla, Phe, Val, and Cit, an aryl, and a heteroaryl group, the aryl and heteroaryl groups being alkyl, haloalkyl, halogen, biphenyl, nitro, nitrile, -OH, -NH ２ , alkylamino, dialkylamino, thiol, thioalkyl, guanidine, urea, carboxylic acid, alkoxyl, carboxamide, carboxylic acid ester, alkyl-C(O)O-, alkylamino-C(O)-, dialkylamino-C(O)-; J is -NH ２ , N ３ , thio, cyclooctyne, -OH, -CO ２ H, transcyclooctene, alkynyl, propargyl, 【Chemical 29】 is a reactive group selected from In the formula, R ３２ is selected from Cl, Br, F, mesylate, and tosylate; R ３３ is selected from Cl, Br, I, F, OH, —O—N-succinimidyl, —O-(4-nitrophenyl), —O-pentafluorophenyl, or —O-tetrafluorophenyl; R ３４ The glucocorticoid agonist compound of claim 18, wherein is H, Me, tetrazine-H, and tetrazine-Me.

22. Possessing the structure of formula (III): 【Chemistry 30】 During the ceremony, Y is CH ２ and O; E is CH ２ and O; G is selected from CH and N; L is selected from H and F; R ５ But -CH ２ OH, -SCH ２ F, and 【Chemistry 31】 is selected from A １ and A ２ is independently selected from H and F; V may be selected from an alkyl chain of 1 to 8 carbons, a linear or branched polyethylene oxide group containing 1 to 13 units, a linear or branched alkyl group containing 1 to 8 carbons, -O-alkyl, a carboxylic acid, a carboxamide, a carboxylic acid ester, alkyl-C(O)O-, alkylamino-C(O)-, dialkylamino-C(O)-, a sequence of 1 to 3 amino acids, each amino acid being independently selected from Glu, Gly, Asn, Asp, Gln, Leu, Lys, Ala, βAla, Phe, Val, and Cit, an aryl, and a heteroaryl group, the aryl and heteroaryl groups being alkyl, haloalkyl, halogen, biphenyl, nitro, nitrile, -OH, -NH ２ , alkylamino, dialkylamino, thiol, thioalkyl, guanidine, urea, carboxylic acid, alkoxyl, carboxamide, carboxylic acid ester, alkyl-C(O)O-, alkylamino-C(O)-, dialkylamino-C(O)-; J is -NH ２ , N ３ , thio, cyclooctyne, -OH, -CO ２ H, transcyclooctene, alkynyl, propargyl, 【Chemistry 32】 is a reactive group selected from In the formula, R ３２ is selected from Cl, Br, F, mesylate, and tosylate; R ３３ is selected from Cl, Br, I, F, OH, —O—N-succinimidyl, —O-(4-nitrophenyl), —O-pentafluorophenyl, or —O-tetrafluorophenyl; R ３４ The glucocorticoid agonist compound of claim 18, wherein is H, Me, tetrazine-H, and tetrazine-Me. 【Request 23】 【Chemical 33-1】 【Chemistry 33-2】 【Chemistry 33-3】 【Chemistry 33-4】 23. The compound according to claim 18, 21 or 22, selected from:

24. X or Z may be spiro[3.3]heptane or [1.1.1]bicyclopentane, and Y is CH ２ or O.

25. 25. An antibody drug conjugate (ADC) comprising an antibody or antibody binding fragment thereof, preferably one that binds to an antigen expressed by an immune cell, preferably a human immune cell, wherein the antibody or antibody binding fragment is attached to at least one glucocorticoid agonist compound or steroid-linker according to any one of claims 1 to 11 and 18 to 24. 【Request 26】 【Chemical 34-1】 【Chemistry 34-2】 【Chemistry 34-3】 【Chemistry 34-4】 【Chemistry 34-5】 is selected from 26. The ADC of claim 25, wherein preferably, n=2-12, 2-10, 2-8, 2-6, or 2-4, and A is an antibody that binds to an antigen expressed by an immune cell, preferably a human immune cell, more preferably an anti-human VISTA antibody.

27. A steroid-linker payload comprising a glucocorticoid agonist according to any one of claims 1 to 6, 11 and 18 to 24, wherein the linker is selected from any of those disclosed herein or exemplified in the Examples.

28. PAB and / or amino acids or peptides, optionally 1 to 12 amino acids, further optionally a dipeptide, tripeptide, quattrapeptide, pentapeptide, further optionally Gly, Asn, Asp, Gln, Leu, Lys, Ala, Phe, Cit, Val, Val-Cit, Val-Ala, Val-Gly, Val-Gln, Ala-Val, Cit-Cit, Lys-Val-Cit, Asp-Val-Ala, Ala-Ala-Asn, Asp-Val-Ala, Ala-Val 25. A steroid-linker payload comprising the glucocorticoid agonist of any one of claims 1 to 6, 11 and 18 to 24, comprising at least one cleavable or non-cleavable linker selected from Asp-Val-Cit, Ala-Asn-Val, βAla-Leu-Ala-Leu, Lys-Val-Ala, Val-Leu-Lys, Asp-Val-Cit, Val-Ala-Val, and Ala-Ala-Asn, or optionally at least one of GlcA, PAB, and Glu-Gly.

29. 25. A steroid-linker payload comprising at least one glucocorticoid agonist compound according to any one of claims 1 to 6, 11 and 18 to 24, comprising at least one cleavable linker and / or sacrificial linker attached directly or indirectly to the glucocorticoid agonist steroid compound.

30. 30. An antibody drug conjugate (ADC) comprising an antibody or antibody binding fragment thereof, preferably one that binds to an antigen expressed by an immune cell, preferably an antigen expressed on a human immune cell, wherein the antibody or antibody binding fragment is attached to at least one glucocorticoid agonist or steroid-linker compound according to any one of claims 1 to 11, 18 to 24 and 27 to 29. 【Request 31】 【Chemical 35-1】 【Chemistry 35-2】 【Chemistry 35-3】 【Chemistry 35-4】 【Chemistry 35-5】 is selected from 31. The ADC of claim 30, wherein preferably, n=2-12, 2-10, 2-8, 2-6, or 2-4, and A is an antibody that binds to an antigen expressed by an immune cell, preferably a human immune cell, more preferably an anti-human VISTA antibody.

32. 32. A composition comprising at least one glucocorticoid agonist compound or steroid linker conjugate or ADC according to any one of claims 1 to 31 and a pharma- ceutically acceptable carrier.

33. 33. The composition of claim 32, suitable for in vivo administration to a subject in need thereof.

34. 34. The composition of claim 32 or 33, comprising at least one additive.

35. 35. The composition of claim 32, 33 or 34, comprising at least one stabilizing or buffering agent.

36. A composition according to any one of claims 32 to 35, suitable for parenteral administration, optionally by injection.

37. 37. The composition of any one of claims 32 to 36, which is suitable for injection into a subject in need thereof, optionally via intravenous, subcutaneous, intramuscular, intratumoral, intranodal, intranasal, or intrathecal injection.

38. The composition according to any one of claims 32 to 37, which is administrable subcutaneously.

39. 39. The composition of any one of claims 32 to 38, contained in a device providing subcutaneous administration selected from the group consisting of a syringe, an injection device, an infusion pump, an injector pen, a needle-free device, an auto-injector, and a subcutaneous patch delivery system.

40. 40. The device of claim 39, which delivers a fixed dose of the glucocorticoid receptor agonist to the patient.

41. A medicament comprising at least one glucocorticoid agonist compound or a steroid linker conjugate or ADC according to any one of claims 1 to 31 or a composition containing same according to any one of claims 32 to 39 for treatment and / or prevention.

42. 42. The method of claim 41 for the treatment of allergy, autoimmunity, transplantation, gene therapy, inflammation, GVHD, or sepsis in a human subject, or for treating or preventing inflammatory, autoimmune, or allergic side effects associated with any of the foregoing conditions.

43. The medicament according to any one of claims 41 to 42, which is for acute use.

44. The medicament according to any one of claims 41 to 42, which is for chronic use.

45. The method according to any one of claims 41 to 42, which is for maintenance therapy.

46. For the treatment or prevention of acute or chronic inflammation and autoimmune and inflammatory indications associated therewith, said condition being, optionally, among others, acquired aplastic anemia+, acquired hemophilia+, acute disseminated encephalomyelitis (ADEM)+, acute hemorrhagic leukoencephalitis (AHLE) / Hurst disease+, primary agammaglobulinemia+, alopecia areata+, ankylosing spondylitis (AS), anti-NMDA receptor encephalitis+, antiphospholipid syndrome (APS)+, arteriosclerosis, autism spectrum disorder (ASD), autoimmune Addison's disease (AAD)+, autoimmune autonomic neuropathy / autoimmune autonomic neuropathy. Autoimmune ganglionopathy (AAG), autoimmune encephalitis+, autoimmune gastritis, autoimmune hemolytic anemia (AIHA)+, autoimmune hepatitis (AIH)+, autoimmune hyperlipidemia, autoimmune hypophysitis / lymphocytic hypophysitis+, autoimmune inner ear disease (AIED)+, autoimmune lymphoproliferative syndrome (ALPS)+, autoimmune myocarditis, autoimmune oophoritis+, autoimmune orchitis+, autoimmune pancreatitis (AIP) / immunoglobulin G4-related disease (IgG4-RD)+, autoimmune polyglandular syndrome types I, II, and III+, autoimmune progesterone dermatitis+, autoimmune sudden deafness (SNHL) , achalasia, Addison's disease, adult Still's disease, agammaglobulinemia, alopecia areata, amyloidosis, ankylosing spondylitis, anti-GBM / anti-TBM nephritis, antiphospholipid syndrome, autoimmune angioedema, autoimmune autonomic neuropathy, autoimmune encephalomyelitis, autoimmune hepatitis, autoimmune inner ear disease (AIED), autoimmune myocarditis, autoimmune oophoritis, autoimmune orchitis, autoimmune pancreatitis, autoimmune retinopathy, autoimmune urticaria, axonal and neuronal neuropathy (AMAN), Baro's disease, Behçet's disease, benign mucous membrane pemphigoid, bullous pemphigoid, Castleman's disease (CD), parsley, Acck's disease, Chagas' disease, chronic inflammatory demyelinating polyneuropathy (CIDP), chronic relapsing multifocal osteomyelitis (CRMO), Churg-Strauss syndrome (CSS) or eosinophilic granulomatosis (EGPA), cicatricial pemphigoid, Cogan's syndrome, cold agglutinin disease, congenital heart block, Coxsackie myocarditis, CREST syndrome, type 1 diabetes, dermatitis herpetiformis, dermatomyositis, Devic's disease (neuromyelitis optica), discoid lupus, Dressler's syndrome, endometriosis, eosinophilic esophagitis (EoE), eosinophilic fasciitis, erythema nodosum, essential mixed cryoglobulinemia, Evans' syndrome, fibromyalgia,Fibrotic alveolitis, fibrosing alveolitis, giant cell myocarditis, glomerulonephritis, Goodpasture's syndrome, granulomatosis with polyangiitis, Graves' disease, Guillain-Barré syndrome, Hashimoto's thyroiditis, hemolytic anemia, Henoch-Schonlein purpura (HSP), herpes gestationis or pemphigoid of gestationis (PG), sweat gland suppuration (HS) (acne contralateralis), hypogammaglobulinemia, IgA nephropathy, IgG4-related sclerosing disease, immune thrombocytopenic purpura (ITP), inclusion body myositis (IBM), interstitial cystitis (IC), juvenile arthritis, juvenile diabetes mellitus (type 1 diabetes), juvenile myositis (JM), Kawasaki disease, Ran Bart-Eaton syndrome, leukocytoclastic vasculitis, lichen planus, lichen sclerosus, lignified conjunctivitis, linear immunoglobulin A disease (LAD), lupus (including nephritic and cutaneous), chronic Lyme disease, Meniere's disease, microscopic polyangiitis (MPA), mixed connective tissue disease (MCTD), Mooren's ulcer, Mukka-Habermann disease, polymotor neuropathy (MMN) or MMNCB, multiple sclerosis, myasthenia gravis, myelin oligodendrocyte glycoprotein antibody disorder, myositis, narcolepsy, neonatal lupus, neuromyelitis optica, neutropenia, ocular cicatricial pemphigoid, optic neuritis, opsoclonus, rheumatoid arthritis ... OMS, relapsing rheumatoid arthritis (PR), PANDAS, paraneoplastic cerebellar degeneration (PCD), paroxysmal nocturnal hemoglobinuria (PNH), Parry-Romberg syndrome, pars planitis (peripheral uveitis), Parsonage-Turner syndrome, pemphigus, peripheral neuropathy, perivenous encephalomyelitis, pernicious anemia (PA), POEMS syndrome, polyarteritis nodosa, polyglandular syndrome types I, II, III, polymyalgia rheumatica, polymyositis, post-myocardial infarction syndrome, post-pericardiotomy syndrome, primary biliary cholangitis, primary sclerosing cholangitis, progesterone dermatitis, psoriasis, psoriasis Arthritis, Pure Red Cell Aplasia (PRCA), Pyoderma Gangrenosum, Raynaud's Phenomenon, Reactive Arthritis, Reflex Sympathetic Dystrophy, Relapsing Polychondritis, Restless Legs Syndrome (RLS), Retroperitoneal Fibrosis, Rheumatic Fever, Rheumatoid Arthritis, Sarcoidosis, Schmidt's Syndrome, Scleritis, Scleroderma, Sjogren's Syndrome, Sperm and Testicular Autoimmunity, Stiff Person Syndrome (SPS), Subacute Bacterial Endocarditis (SBE), Susac's Syndrome, Sympathetic Ophthalmia (SO), Takayasu's Arteritis, Temporal Arteritis / Giant Cell Arteritis, Thrombocytopenic Purpura (TTP), Thyroid Eye Disease (TED),The medicament according to any one of claims 41 to 45, comprising Tolosa-Hunt syndrome (THS), transverse myelitis, type 1 diabetes, undifferentiated connective tissue disease (UCTD), uveitis, vasculitis, vitiligo, and Vogt-Koyanagi-Harada disease.

47. 47. A medicament according to any one of claims 41 to 46 for the treatment or prevention of acute or chronic inflammation and associated autoimmune and inflammatory and allergic indications or side effects, said conditions optionally including severe asthma, giant cell arteritis, ANKA vasculitis, and IBD (colitis and Crohn's disease).

48. The medicament according to any one of claims 41 to 47, which is for the treatment or prevention of a condition selected from rheumatoid arthritis, juvenile idiopathic arthritis, psoriatic arthritis, ankylosing spondylitis, adult Crohn's disease, pediatric Crohn's disease, ulcerative colitis, plaque psoriasis, hidradenitis suppurativa, uveitis, Behcet's disease, spondyloarthropathy, or psoriasis.

49. One or more of the following: (i) chronic, acute, or episodic allergic, inflammatory, or inflammatory conditions, e.g., chronic, acute, episodic, remitting / relapsing; (ii) conditions that are only primarily treatable effectively with high doses of steroids, optionally polymyalgia rheumatica and / or giant cell arteritis, where the patient is optionally being treated or being treated with high doses of steroids; (iii) conditions with comorbidities limiting steroid use, optionally diabetes mellitus, non-alcoholic steatohepatitis (NASH), morbid obesity, avascular / osteonecrosis (AVN), glaucoma, steroid-induced hypertension, severe skin fragility, and / or osteoarthritis; (iv) AAV, polymyositis, dermatomyositis, lupus, inflammatory lung disease, autoimmune hepatitis, inflammatory bowel disease, immune thrombocytopenia, autoimmune hemolytic anemia, gout patients in conditions where safe long-term treatments are available but induction with high doses of steroids for several months is desirable, optionally where induction with high doses of steroids for several months is therapeutically justified; (v) Skin conditions requiring short / long term treatment, optionally conditions of uncertain treatment or duration and / or conditions with no effective alternative to steroid administration, optionally other severe immune-related skin conditions such as Stevens-Johnson, other severe drug rash conditions, conditions with widespread contact dermatitis, PG, LCV, erythroderma, and the like; (vi) conditions treated with high dose corticosteroids for exacerbations / recurrences, optionally COPD, asthma, lupus, gout, pseudogout, (vii) immune-related neurological disorders such as small fiber neuropathy, MS (subset), chronic inflammatory demyelinating polyneuropathy, myasthenia gravis, and the like; (viii) optionally hematology / oncology indications where high doses of steroids are therapeutically justified or beneficial; (ix) an ophthalmic condition, optionally uveitis, iritis, scleritis, and the like; (x) conditions associated with permanent or very long-term adrenal insufficiency or secondary adrenal insufficiency, optionally, iatrogenic Addisonian crisis; (xi) A medicament according to any one of claims 41 to 48 for the treatment or prevention in patients with conditions that are often treated with long-term low dose steroids, optionally lupus, RA, psA, vasculitis and the like.

50. 50. The medicament according to any one of claims 41 to 49, for the treatment or prophylaxis in special classes of patients at risk of toxicity in steroid treatment, such as pregnant / lactating women, pediatric patients, optionally with growth disorders or cataracts, said patients being additionally treated with another active agent.

51. 51. The agent of any one of claims 41 to 50, wherein the patient is further treated with an immunomodulatory antibody or fusion protein selected from an immunoinhibitory antibody or fusion protein targeting one or more of CTLA4, PD-1, PDL-1, LAG-3, TIM-3, BTLA, B7-H4, B7-H3, VISTA, and / or an agonistic antibody or fusion protein targeting one or more of CD40, CD137, OX40, GITR, CD27, CD28, or ICOS.

52. 52. The antibody drug conjugate (ADC), agent or composition of any one of claims 13-17, 25-26, 30-39 and 41-51, wherein the ADC comprises an antibody or antigen-binding fragment ("A") that comprises an antigen-binding region that specifically binds human V domain Ig inhibitor of T cell activation (human VISTA), and wherein the ADC, upon administration to a subject in need thereof, is preferentially delivered to one or more of VISTA-expressing immune cells, optionally monocytes, myeloid cells, T cells, Tregs, NK cells, neutrophils, dendritic cells, macrophages, eosinophils, and endothelial cells, resulting in functional internalization of the anti-inflammatory agent into one or more of the immune cells.

53. 53. The antibody drug conjugate (ADC), agent or composition of any one of claims 13-17, 25-26, 30-39 and 41-52, wherein the ADC optionally comprises an anti-human VISTA antibody or antibody fragment that preferentially binds to VISTA expressing cells at physiological pH (≈7.5) with a pK of at most 70 hr in human VISTA knock-in rodents.

54. 54. The antibody drug conjugate (ADC), agent or composition of any one of claims 13-17, 25-26, 30-39 and 41-53, wherein the ADC comprises an anti-human VISTA antibody or antibody fragment that binds to t0 VISTA expressing cells at physiological pH and has a pK of at most 3.5±0.5 days in cynomolgus monkeys or humans at physiological pH, more typically at most 48 hours, at most 24 hours, at most 18 hours, or at most 12 hours.

55. 55. The antibody drug conjugate (ADC), agent or composition of any one of claims 13-17, 25-26, 30-39 and 41-54, wherein the ADC comprises an anti-human VISTA antibody or antibody fragment having a pK of at most 2.8 or 2.3 or 1.5 days, or 1 day, or 12 hours or 8 hours ± 0.5 days in cynomolgus monkeys or humans at physiological pH.

56. 56. The antibody drug conjugate (ADC), agent or composition of any one of claims 13-17, 25-26, 30-39 and 41-55, wherein the ADC comprises an anti-human VISTA antibody or antibody fragment having a pK of at most 6-12 hours in human VISTA rodents at physiological pH.

57. 57. The antibody drug conjugate (ADC), agent or composition of any one of claims 13-17, 25-26, 30-39 and 41-56, wherein the ADC comprises an anti-human VISTA antibody or antibody fragment comprising a linker that is cleaved upon internalization of the ADC into a VISTA-expressing immune cell, optionally one or more of T cells, Tregs, NK cells, neutrophils, monocytes, myeloid cells, dendritic cells, macrophages, eosinophils, and endothelial cells, resulting in release of a therapeutically effective amount of an anti-inflammatory agent within the immune cell, which elicits anti-inflammatory activity.

58. 58. The antibody drug conjugate (ADC), agent or composition of any one of claims 13-17, 25-26, 30-39 and 41-57, wherein the ADC comprises an anti-human VISTA antibody or antibody fragment, and the anti-VISTA antibody or antigen-binding fragment has an in vivo serum half-life of about 2.3 days in a primate, optionally a cynomolgus monkey, at physiological pH (about pH 7.5).

59. 59. The antibody drug conjugate (ADC), agent or composition of any one of claims 13-17, 25-26, 30-39 and 41-58, wherein the ADC comprises an anti-human VISTA antibody or antibody fragment, and the anti-VISTA antibody or antigen-binding fragment has an in vivo serum half-life in serum at physiological pH (about pH 7.5) of 70 hours or less, 60 hours or less, 50 hours or less, 40 hours or less, 30 hours or less, 24 hours or less, 22-24 hours or less, 20-22 hours or less, 18-20 hours or less, 16-18 hours or less, 14-16 hours or less, 12-14 hours or less, 10-12 hours or less, 8-10 hours or less, 6-8 hours or less, 4-6 hours or less, 2-4 hours or less, 1-2 hours or less, 0.5-1.0 hours or less, or 0.1-0.5 hours or less in human VISTA knock-in rodents.

60. 60. The antibody drug conjugate (ADC), agent or composition of any one of claims 13-17, 25-26, 30-39 and 41-59, wherein the ADC comprises an anti-human VISTA antibody or antibody fragment and the PD / PK ratio of the ADC, when used in vivo, is at least 2:1, 3:1, 4:1, 5:1, 6:1, 7:1, 8:1, 9:1, 10:1, 11:1, 12:1, 13:1, 14:1, 28:1 or more in a human VISTA knock-in rodent, or a human or non-human primate, optionally a cynomolgus monkey.

61. 61. The antibody drug conjugate (ADC), agent or composition of any one of claims 13-17, 25-26, 30-39 and 41-60, wherein the ADC comprises an anti-human VISTA antibody or antibody fragment, and the PD of the ADC is at least 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, or 28 days, 2-3 weeks, 1 month, 2 months, or longer in any one of a rodent, or a human or non-human primate, optionally a cynomolgus monkey.

62. 62. The antibody drug conjugate (ADC), agent or composition of any one of claims 13-17, 25-26, 30-39 and 41-61, wherein the ADC comprises an anti-human VISTA antibody or antibody fragment, the anti-human VISTA antibody comprising an Fc region with impaired or intact FcR binding.

63. 63. The antibody drug conjugate (ADC), agent or composition of any one of claims 13-17, 25-26, 30-39 and 41-62, wherein the ADC comprises an antibody or antibody fragment, optionally an anti-human VISTA antibody or antibody fragment, wherein the antibody or antibody fragment comprises a human IgG1, IgG2, IgG3, or IgG4 Fc region with impaired or intact FcR binding.

64. 64. The antibody drug conjugate (ADC), agent or composition of any one of claims 13-17, 25-26, 30-39 and 41-63, wherein the ADC comprises an antibody or antibody fragment, optionally an anti-human VISTA antibody or antibody fragment, wherein the antibody or antibody fragment comprises a human IgG1 Fc region with impaired FcR binding.

65. The antibody drug conjugate (ADC), agent or composition of any one of claims 13-17, 25-26, 30-39 and 41-64, wherein the ADC comprises an antibody or antibody fragment, optionally an anti-human VISTA antibody or antibody fragment, comprising a human or non-human primate constant or Fc region that has been modified to impair or eliminate binding to at least two native human Fc gamma receptors.

66. 66. The antibody drug conjugate (ADC), agent or composition of any one of claims 13-17, 25-26, 30-39 and 41-65, wherein the ADC comprises an antibody or antibody fragment, optionally an anti-human VISTA antibody or antibody fragment, comprising a human or non-human primate constant or Fc region that has been modified to impair or eliminate binding to any one, two, three, four or all five of the following FcRs: hFcγRI (CD64), FcyRIIA or hFcyRIIB, (CD32 or CD32A), and FcγRlllA (CD16A) or FcγRlllB (CD16B).

67. 67. The antibody drug conjugate (ADC), agent or composition of any one of claims 13-17, 25-26, 30-39 and 41-66, wherein the ADC comprises an antibody or antibody fragment, optionally an anti-human VISTA antibody or antibody fragment, comprising a human IgG2 kappa backbone, optionally with V234A / G237A / P238S / H268A / V309L / A330S / P331S silencing mutations in the Fc region.

68. The ADC comprises an antibody or antibody fragment, optionally an anti-human VISTA antibody or antibody fragment, optionally comprising a L234A / L235A silencing mutation in the Fc region, and optionally a complement (C1 Ｑ 68. The antibody drug conjugate (ADC), agent or composition of any one of claims 13-17, 25-26, 30-39 and 41-67, comprising an IgG1 / kappa backbone having a mutation that impairs IgG1 / kappa binding.

69. The antibody drug conjugate (ADC), agent or composition of any one of claims 13-17, 25-26, 30-39 and 41-68, wherein the ADC comprises an antibody or antibody fragment, optionally an anti-human VISTA antibody or antibody fragment, comprising a human IgG1 / kappa backbone, optionally with L234A / L235A silencing mutations and E269R and E233A mutations in the Fc region.

70. 70. The antibody drug conjugate (ADC), agent or composition of any one of claims 13-17, 25-26, 30-39 and 41-69, wherein the ADC comprises an anti-human VISTA antibody or antibody fragment, and binding of the anti-VISTA antibody or antigen-binding fragment to a VISTA-expressing immune cell does not directly agonize or antagonize a VISTA-mediated effect on immunity.

71. 71. The antibody drug conjugate (ADC), agent or composition of any one of claims 13-17, 25-26, 30-39 and 41-70, wherein the ADC comprises an antibody or antibody fragment, optionally an anti-human VISTA antibody or antibody fragment, comprising a human IgG1, IgG2, IgG3, or IgG4 Fc region, and wherein intrinsic FcR binding is intact.

72. 72. The antibody drug conjugate (ADC), agent or composition of any one of claims 13-17, 25-26, 30-39 and 41-71, wherein the ADC comprises an antibody or antibody fragment, optionally an anti-human VISTA antibody or antibody fragment, comprising a native (unmodified) human IgG2 Fc region.

73. 73. The antibody drug conjugate (ADC), agent or composition of any one of claims 13-17, 25-26, 30-39 and 41-72, wherein the ADC comprises an antibody or antibody fragment, optionally an anti-human VISTA antibody or antibody fragment, and the antibody or antigen-binding fragment comprises a K in the range of 0.0001 nM to 10.0 nM, 0.001 to 1.0 nM, or 0.01 to 0.7 or less, as determined by surface plasmon resonance (SPR) at 24°C or 37°C.

74. 74. The antibody drug conjugate (ADC), agent or composition of any one of claims 13-17, 25-26, 30-39 and 41-73, wherein the ADC comprises an antibody or antibody fragment, optionally an anti-human VISTA antibody or antibody fragment, and the antibody or antigen-binding fragment comprises a KD of 0.13 to 0.64 nM as determined by surface plasmon resonance (SPR) at 24°C or 37°C.

75. 75. The antibody drug conjugate (ADC), agent or composition of any one of claims 13-17, 25-26, 30-39 and 41-74, wherein the ADC optionally comprises an antibody or antibody fragment, optionally an anti-human VISTA antibody or antibody fragment, and the drug antibody ratio is in the range of 1:1 to 12:

1.

76. 76. The antibody drug conjugate (ADC), agent or composition of any one of claims 13-17, 25-26, 30-39 and 41-75, wherein the ADC optionally comprises an antibody or antibody fragment, optionally an anti-human VISTA antibody or antibody fragment, and the drug to antibody ratio is in the range of 2-12:1, 2-8:1, 4-8:1, or 6-8:

1.

77. 77. The antibody drug conjugate (ADC), agent or composition of any one of claims 13-17, 25-26, 30-39 and 41-76, wherein the ADC optionally comprises an anti-human VISTA antibody or antibody fragment, and the drug antibody ratio is about 8:1 (n=8) or about 4:1 (n=4).

78. 80. The antibody drug conjugate (ADC), agent or composition of any one of claims 13-17, 25-26, 30-39 and 41-77, wherein the ADC comprises an antibody or antibody fragment, optionally an anti-human VISTA antibody or antibody fragment, that internalizes one or more of monocytes, myeloid cells, T cells, Tregs, CD4 T cells, CD8 T cells, macrophages, NK cells, macrophages, eosinophils, mast cells, B cells, and neutrophils.

79. 80. The antibody drug conjugate (ADC), agent or composition of any one of claims 13-17, 25-26, 30-39 and 41-78, wherein the ADC comprises an antibody or antibody fragment, optionally an anti-human VISTA antibody or antibody fragment, that does not appreciably internalize B cells.

80. 80. The antibody drug conjugate (ADC), agent or composition of any one of claims 13-17, 25-26, 30-39 and 41-79, wherein the ADC comprises an antibody or antibody fragment, optionally an anti-human VISTA antibody or antibody fragment, that, when administered to a subject in need thereof, promotes efficacy and / or reduces adverse side effects, such as toxicity, associated with the anti-inflammatory agent compared to the same dose of the anti-inflammatory agent administered in naked (unconjugated) form.

81. 81. The antibody drug conjugate (ADC), agent or composition of any one of claims 13-17, 25-26, 30-39 and 41-80, wherein the ADC comprises an antibody or antibody fragment, optionally an anti-human VISTA antibody or antibody fragment, and the glucocorticoid is optionally conjugated to the antibody or antigen-binding fragment via an interchain disulfide.

82. 82. The antibody drug conjugate (ADC), agent or composition of any one of claims 13-17, 25-26, 30-39 and 41-81, wherein the ADC comprises an antibody or antibody fragment, optionally an anti-human VISTA antibody or antibody fragment, comprising an esterase-sensitive linker.

83. 83. The antibody drug conjugate (ADC), agent or composition of any one of claims 13-17, 25-26, 30-39 and 41-82, wherein the ADC comprises an antibody or antibody fragment, optionally an anti-human VISTA antibody or antibody fragment, and the cleavable linker is susceptible to one or more of acid-induced cleavage, photo-induced cleavage, peptidase-induced cleavage, esterase-induced cleavage, and disulfide bond cleavage.

84. 84. The antibody drug conjugate (ADC), agent or composition of any one of claims 13-17, 25-26, 30-39 and 41-83, wherein the ADC comprises an antibody or antibody fragment, optionally an anti-human VISTA antibody or antibody fragment, and the antigen-binding fragment comprised in the ADC comprises a Fab, F(ab')2, or scFv antibody fragment.

85. the ADC comprises an anti-human VISTA antibody or antibody fragment, the anti-VISTA antibody or antibody fragment comprised therein being, or optionally: (i) V of SEQ ID NOs: 100, 101, and 102 Ｈ CDRs and V of SEQ ID NOs: 103, 104, and 105 Ｌ those comprising CDRs, (ii) V of SEQ ID NOs: 110, 111, and 112 Ｈ CDRs and V of SEQ ID NOs: 113, 114, and 115 Ｌ those comprising CDRs, (iii) V of SEQ ID NOs: 120, 121, and 122 Ｈ CDRs and V of SEQ ID NOs: 123, 124, and 125 Ｌ those comprising CDRs, (iv) V of SEQ ID NOs: 130, 131, and 132 Ｈ CDRs and V of SEQ ID NOs: 133, 134, and 135 Ｌ those comprising CDRs, (v) V of SEQ ID NOs: 140, 141, and 142 Ｈ CDRs and V of SEQ ID NOs: 143, 144, and 145 Ｌ those comprising CDRs, (vi) V of SEQ ID NOs: 150, 151, and 152 Ｈ CDRs and V of SEQ ID NOs: 153, 154, and 155 Ｌ those comprising CDRs, (vii) V of SEQ ID NOs: 160, 161, and 162 Ｈ CDRs and V of SEQ ID NOs: 163, 164, and 165 Ｌ those comprising CDRs, (viii) V of SEQ ID NOs: 170, 171, and 172 Ｈ CDRs and V of SEQ ID NOs: 173, 174, and 175 Ｌ those comprising CDRs, (ix) V of SEQ ID NOs: 180, 181, and 182 Ｈ CDRs and V of SEQ ID NOs: 183, 184, and 185 Ｌ those comprising CDRs, (x) V of SEQ ID NOs: 190, 191, and 192 Ｈ CDRs and V of SEQ ID NOs: 193, 194, and 195 Ｌ those comprising CDRs, (xi) V of SEQ ID NOs: 200, 201, and 202 Ｈ CDRs and V of SEQ ID NOs: 203, 204, and 205 Ｌ those comprising CDRs, (xii) V of SEQ ID NOs: 210, 211, and 212 Ｈ CDRs and V of SEQ ID NOs: 213, 214, and 215 Ｌ those comprising CDRs, (xiii) V of SEQ ID NOs: 220, 221, and 222 Ｈ CDRs and V of SEQ ID NOs: 223, 224, and 225 Ｌ those comprising CDRs, (xiv) V of SEQ ID NOs: 230, 231, and 232 Ｈ CDRs and V of SEQ ID NOs: 233, 234, and 235 Ｌ those comprising CDRs, (xv) V of SEQ ID NOs: 240, 241, and 242 Ｈ CDRs and V of SEQ ID NOs: 243, 244, and 245 Ｌ those comprising CDRs, (xvi) V of SEQ ID NOs: 250, 251, and 252 Ｈ CDRs and V of SEQ ID NOs: 253, 254, and 255 Ｌ those comprising CDRs, (xvii) the VH CDRs of SEQ ID NOs: 260, 261, and 262, and the VH CDRs of SEQ ID NOs: 263, 264, and 265. Ｌ those comprising CDRs, (xviii) V of SEQ ID NOs: 270, 271, and 272 Ｈ CDRs and V of SEQ ID NOs: 273, 274, and 275 Ｌ those comprising CDRs, (xix) V of SEQ ID NOs: 280, 281, and 282 Ｈ CDRs and V of SEQ ID NOs: 283, 284, and 285 Ｌ those comprising CDRs, (xx) V of SEQ ID NOs: 290, 291, and 292 Ｈ CDRs and V of SEQ ID NOs: 293, 294, and 295 Ｌ those comprising CDRs, (xxi) V of SEQ ID NOs: 300, 301, and 302 Ｈ CDRs and V of SEQ ID NOs: 303, 304, and 305 Ｌ those comprising CDRs, (xxii) V of SEQ ID NOs: 310, 311, and 312 Ｈ CDRs and V of SEQ ID NOs: 313, 314, and 315 Ｌ those comprising CDRs, (xxiii) V of SEQ ID NOs: 320, 321, and 322 Ｈ CDRs and V of SEQ ID NOs: 323, 324, and 325 Ｌ those comprising CDRs, (xxiv) V of SEQ ID NOs: 330, 331, and 332 Ｈ CDRs and V of SEQ ID NOs: 333, 334, and 335 Ｌ those comprising CDRs, (xxv) V of SEQ ID NOs: 340, 341, and 342 Ｈ CDRs and V of SEQ ID NOs: 343, 344, and 345 Ｌ those comprising CDRs, (xxvi) V of SEQ ID NOs: 350, 351, and 352 Ｈ CDRs and V of SEQ ID NOs: 353, 354, and 355 Ｌ those comprising CDRs, (xxvii) V of SEQ ID NOs: 360, 361, and 362 Ｈ CDRs and V of SEQ ID NOs: 363, 364, and 365 Ｌ those comprising CDRs, (xxviii) V of SEQ ID NOs: 370, 371, and 372 Ｈ CDRs and V of SEQ ID NOs: 373, 374, and 375 Ｌ those comprising CDRs, (xxix) V of SEQ ID NOs: 380, 381, and 382 Ｈ CDRs and V of SEQ ID NOs: 383, 384, and 385 Ｌ those comprising CDRs, (xxx) V of SEQ ID NOs: 390, 391, and 392 Ｈ CDRs and V of SEQ ID NOs: 393, 394, and 395 Ｌ those comprising CDRs, (xxxi) V of SEQ ID NOs: 400, 401, and 402 Ｈ CDRs and V of SEQ ID NOs: 403, 404, and 405 Ｌ those comprising CDRs, (xxxii) V of SEQ ID NOs: 410, 411, and 412 Ｈ CDRs and V of SEQ ID NOs: 413, 414, and 415 Ｌ those comprising CDRs, (xxxiii) V of SEQ ID NOs: 420, 421, and 422 Ｈ CDRs and V of SEQ ID NOs: 423, 424, and 425 Ｌ those comprising CDRs, (xxxiv) V of SEQ ID NOs: 430, 431, and 432 Ｈ CDRs and V of SEQ ID NOs: 433, 434, and 435 Ｌ those comprising CDRs, (xxxv) V of SEQ ID NOs: 440, 441, and 442 Ｈ CDRs and V of SEQ ID NOs: 443, 444, and 445 Ｌ those comprising CDRs, (xxxvi) V of SEQ ID NOs: 450, 451, and 452 Ｈ CDRs and V of SEQ ID NOs: 453, 454, and 455 Ｌ those comprising CDRs, (xxxvii) V of SEQ ID NOs: 460, 461, and 462 Ｈ CDRs and V of SEQ ID NOs: 463, 464, and 465 Ｌ those comprising CDRs, (xxxviii) V of SEQ ID NOs: 470, 471, and 472 Ｈ CDRs and V of SEQ ID NOs: 473, 474, and 475 Ｌ those comprising CDRs, (xxxix) V of SEQ ID NOs: 480, 481, and 482 Ｈ CDRs and V of SEQ ID NOs: 483, 484, and 485 Ｌ those comprising CDRs, (xl) V of SEQ ID NOs: 490, 491, and 492 Ｈ CDRs and the VL CDR polypeptides of SEQ ID NOs: 493, 494, and 495; (xli) V of SEQ ID NOs: 500, 501, and 502 Ｈ CDRs and the VL CDR polypeptides of SEQ ID NOs: 503, 504, and 505; (xlii) V of SEQ ID NOs: 510, 511, and 512 Ｈ CDRs and the VL CDR polypeptides of SEQ ID NOs: 513, 514, and 515; (xliii) V of SEQ ID NOs: 520, 521, and 522 Ｈ CDRs and the VL CDR polypeptides of SEQ ID NOs: 523, 524, and 525; (xliv) V of SEQ ID NOs: 530, 531, and 532 Ｈ CDRs and the VL CDR polypeptides of SEQ ID NOs: 533, 534, and 535; (xlv) V of SEQ ID NOs: 540, 541, and 542 Ｈ CDRs and the VL CDR polypeptides of SEQ ID NOs: 543, 544, and 545; (xlvi) V of SEQ ID NOs: 550, 551, and 552 Ｈ CDRs and the VL CDR polypeptides of SEQ ID NOs: 553, 554, and 555; (xlvii) V of SEQ ID NOs: 560, 561, and 562 Ｈ CDRs and V of SEQ ID NOs: 563, 564, and 565 Ｌ those comprising CDRs, (xlviii) V of SEQ ID NOs: 570, 571, and 572 Ｈ CDRs and V of SEQ ID NOs: 573, 574, and 575 Ｌ those comprising CDRs, (xlix) V of SEQ ID NOs: 580, 581, and 582 Ｈ CDRs and V of SEQ ID NOs: 583, 584, and 585 Ｌ those comprising CDRs, (l) V of SEQ ID NOs: 590, 591, and 592 Ｈ CDRs and V of SEQ ID NOs: 593, 594, and 595 Ｌ those comprising CDRs, (li) V of SEQ ID NOs: 600, 601, and 602 Ｈ CDRs and V of SEQ ID NOs: 603, 604, and 605 Ｌ those comprising CDRs, (lii) V of SEQ ID NOs: 610, 611, and 612 Ｈ CDRs and V of SEQ ID NOs: 613, 614, and 615 Ｌ those comprising CDRs, (liii) V of SEQ ID NOs: 620, 621, and 622 Ｈ CDRs and V of SEQ ID NOs: 623, 624, and 625 Ｌ those comprising CDRs, (liv) V of SEQ ID NOs: 630, 631, and 632 Ｈ CDRs and V of SEQ ID NOs: 633, 634, and 635 Ｌ those comprising CDRs, (lv) V of SEQ ID NOs: 640, 641, and 642 Ｈ CDRs and V of SEQ ID NOs: 643, 644, and 645 Ｌ those comprising CDRs, (lvi) V of SEQ ID NOs: 650, 651, and 652 Ｈ CDRs and V of SEQ ID NOs: 653, 654, and 655 Ｌ those comprising CDRs, (lvii) V of SEQ ID NOs: 660, 661, and 662 Ｈ CDRs and V of SEQ ID NOs: 663, 664, and 665 Ｌ those comprising CDRs, (lviii) V of SEQ ID NOs: 670, 671, and 672 Ｈ CDRs and V of SEQ ID NOs: 673, 674, and 675 Ｌ those comprising CDRs, (lix) V of SEQ ID NOs: 680, 681, and 682 Ｈ CDRs and V of SEQ ID NOs: 683, 684, and 685 Ｌ those comprising CDRs, (lx) V of SEQ ID NOs: 690, 691, and 692 Ｈ CDRs and V of SEQ ID NOs: 693, 694, and 695 Ｌ those comprising CDRs, (lxi) V of SEQ ID NOs: 700, 701, and 702 Ｈ CDRs and V of SEQ ID NOs: 703, 704, and 705 Ｌ those comprising CDRs, (lxii) V of SEQ ID NOs: 710, 711, and 712 Ｈ CDRs and V of SEQ ID NOs: 713, 714, and 715 Ｌ those comprising CDRs, (lxiii) V of SEQ ID NOs: 720, 721, and 722 Ｈ CDRs and V of SEQ ID NOs: 723, 724, and 725 Ｌ those comprising CDRs, (lxiv) V of SEQ ID NOs: 730, 731, and 732 Ｈ CDRs and V of SEQ ID NOs: 733, 734, and 735 Ｌ those comprising CDRs, (lxv) V of SEQ ID NOs: 740, 741, and 742 Ｈ CDRs and V of SEQ ID NOs: 743, 744, and 745 Ｌ those comprising CDRs, (lxvi) V of SEQ ID NOs: 750, 751, and 752 Ｈ CDRs and V of SEQ ID NOs: 753, 754, and 755 Ｌ those comprising CDRs, (lxvii) V of SEQ ID NOs: 760, 761, and 762 Ｈ CDRs and V of SEQ ID NOs: 763, 764, and 765 Ｌ those comprising CDRs, (lxviii) V of SEQ ID NOs: 770, 771, and 772 Ｈ CDRs and V of SEQ ID NOs: 773, 774, and 775 Ｌ those comprising CDRs, (lxix) V of SEQ ID NOs: 780, 781, and 782 Ｈ CDRs and V of SEQ ID NOs: 783, 784, and 785 Ｌ those comprising CDRs, (lxx) V of SEQ ID NOs: 790, 791, and 792 Ｈ CDRs and V of SEQ ID NOs: 793, 794, and 795 Ｌ those comprising CDRs, (lxxi) V of SEQ ID NOs: 800, 801, and 802 Ｈ CDRs and V of SEQ ID NOs: 803, 804, and 805 Ｌ those comprising CDRs, (lxxii) V of SEQ ID NOs: 810, 811, and 812 Ｈ CDRs and V of SEQ ID NOs: 813, 814, and 815 Ｌ 5. The antibody drug conjugate (ADC), agent or composition of any one of claims 13 to 17, 25 to 26, 30 to 39 and 41 to 84, selected from the group consisting of:

86. 86. The antibody drug conjugate (ADC), agent or composition of any one of claims 13-17, 25-26, 30-39 and 41-85, wherein the ADC comprises an anti-VISTA antibody or antibody fragment that comprises the same CDRs as any one of VSTB92, VSTB56, VSTB95, VSTB103, and VSTB66.

87. The ADC is V Ｈ Polypeptides and V Ｌ and an anti-VISTA antibody or antibody fragment comprising a polypeptide, each of which is Ｈ Polypeptides and V Ｌ 1. An antibody comprising a polypeptide, (i) V identical to SEQ ID NO: 106 Ｈ Polypeptide and V of SEQ ID NO: 108 Ｌ those containing polypeptides, (ii) V of SEQ ID NO: 116 Ｈ Polypeptide and V of SEQ ID NO: 118 Ｌ those containing polypeptides, (iii) V of SEQ ID NO: 126 Ｈ Polypeptide and V of SEQ ID NO: 128 Ｌ those containing polypeptides, (iv) V of SEQ ID NO: 136 Ｈ Polypeptide and V of SEQ ID NO: 138 Ｌ those containing polypeptides, (v) V of SEQ ID NO: 146 Ｈ Polypeptide and V of SEQ ID NO: 148 Ｌ those containing polypeptides, (vi) V of SEQ ID NO: 156 Ｈ Polypeptide and V of SEQ ID NO: 158 Ｌ those containing polypeptides, (vii) V of SEQ ID NO: 166 Ｈ Polypeptide and V of SEQ ID NO: 168 Ｌ those containing polypeptides, (viii) V of SEQ ID NO: 176 Ｈ Polypeptide and V of SEQ ID NO: 178 Ｌ those containing polypeptides, (ix) V of SEQ ID NO: 186 Ｈ Polypeptide and V of SEQ ID NO: 188 Ｌ those containing polypeptides, (x) V of SEQ ID NO: 196 Ｈ Polypeptide and V of SEQ ID NO: 198 Ｌ those containing polypeptides, (xi) V of SEQ ID NO: 206 Ｈ Polypeptide and V of SEQ ID NO:208 Ｌ those containing polypeptides, (xii) V of SEQ ID NO: 216 Ｈ Polypeptide and V of SEQ ID NO:218 Ｌ those containing polypeptides, (xiii) V of SEQ ID NO: 226 Ｈ Polypeptide and V of SEQ ID NO:228 Ｌ those containing polypeptides, (xiv) V of SEQ ID NO: 236 Ｈ Polypeptide and V of SEQ ID NO:238 Ｌ those containing polypeptides, (xv) V of SEQ ID NO: 246 Ｈ Polypeptide and V of SEQ ID NO:248 Ｌ those containing polypeptides, (xvi) V of SEQ ID NO: 256 Ｈ Polypeptide and V of SEQ ID NO:258 Ｌ those containing polypeptides, (xvii) V of SEQ ID NO: 266 Ｈ Polypeptides, and V of SEQ ID NO:268 Ｌ those containing polypeptides, (xviii) V of SEQ ID NO: 276 Ｈ A polypeptide and a VL polypeptide of SEQ ID NO: 278; (xix) V of SEQ ID NO: 286 Ｈ Polypeptide and V of SEQ ID NO:288 Ｌ those containing polypeptides, (xx) V of SEQ ID NO: 296 Ｈ Polypeptide and V of SEQ ID NO:298 Ｌ those containing polypeptides, (xxi) V of SEQ ID NO: 306 Ｈ Polypeptides and V of SEQ ID NO:308 Ｌ those containing polypeptides, (xxii) V of SEQ ID NO: 316 Ｈ Polypeptide and V of SEQ ID NO:318 Ｌ those containing polypeptides, (xxiii) V of SEQ ID NO: 326 Ｈ Polypeptide and V of SEQ ID NO:328 Ｌ those containing polypeptides, (xxiv) V of SEQ ID NO: 336 Ｈ Polypeptide and V of SEQ ID NO: 338 Ｌ those containing polypeptides, (xxv) V of SEQ ID NO: 346 Ｈ Polypeptide and V of SEQ ID NO:348 Ｌ those containing polypeptides, (xxvi) V of SEQ ID NO: 356 Ｈ Polypeptide and V of SEQ ID NO:358 Ｌ those containing polypeptides, (xxvii) V of SEQ ID NO: 366 Ｈ Polypeptide and V of SEQ ID NO:368 Ｌ those containing polypeptides, (xxviii) V of SEQ ID NO: 376 Ｈ Polypeptide and V of SEQ ID NO:378 Ｌ those containing polypeptides, (xxix) V of SEQ ID NO: 386 Ｈ Polypeptide and V of SEQ ID NO:388 Ｌ those containing polypeptides, (xxx) V of SEQ ID NO: 396 Ｈ Polypeptide and V of SEQ ID NO:398 Ｌ those containing polypeptides, (xxxi) V of SEQ ID NO: 406 Ｈ Polypeptide and V of SEQ ID NO:408 Ｌ those containing polypeptides, (xxxii) V of SEQ ID NO: 416 Ｈ Polypeptide and V of SEQ ID NO:418 Ｌ those containing polypeptides, (xxxiii) V of SEQ ID NO: 426 Ｈ Polypeptide and V of SEQ ID NO:428 Ｌ those containing polypeptides, (xxxiv) V of SEQ ID NO: 436 Ｈ Polypeptide and V of SEQ ID NO:438 Ｌ those containing polypeptides, (xxxv) V of SEQ ID NO: 446 Ｈ Polypeptide and V of SEQ ID NO:448 Ｌ those containing polypeptides, (xxxvi) V of SEQ ID NO: 456 Ｈ Polypeptide and V of SEQ ID NO:458 Ｌ those containing polypeptides, (xxxvii) V of SEQ ID NO: 466 Ｈ Polypeptide and V of SEQ ID NO: 468 Ｌ those containing polypeptides, (xxxviii) V of SEQ ID NO: 476 Ｈ Polypeptide and V of SEQ ID NO:478 Ｌ those containing polypeptides, (xxxix) V of SEQ ID NO: 486 Ｈ Polypeptide and V of SEQ ID NO:488 Ｌ those containing polypeptides, (xl) V of SEQ ID NO: 496 Ｈ Polypeptide and V of SEQ ID NO:498 Ｌ those containing polypeptides, (xli) V of SEQ ID NO:506 Ｈ Polypeptide and V of SEQ ID NO:508 Ｌ those containing polypeptides, (xlii) V of SEQ ID NO:516 Ｈ Polypeptide and V of SEQ ID NO:518 Ｌ those containing polypeptides, (xliii) V of SEQ ID NO: 526 Ｈ Polypeptide and V of SEQ ID NO:528 Ｌ those containing polypeptides, (xliv) V of SEQ ID NO:536 Ｈ Polypeptides and V of SEQ ID NOs: 533, 534, and 535 Ｌ those containing polypeptides, (xlv) V of SEQ ID NO:546 Ｈ Polypeptide and V of SEQ ID NO:548 Ｌ those containing polypeptides, (xlvi) V of SEQ ID NO:556 Ｈ Polypeptide and V of SEQ ID NO:558 Ｌ those containing polypeptides, (xlvii) V of SEQ ID NO: 566 Ｈ Polypeptide and V of SEQ ID NO:568 Ｌ those containing polypeptides, (xlviii) V of SEQ ID NO: 576 Ｈ Polypeptide and V of SEQ ID NO:578 Ｌ those containing polypeptides, (xlix) V of SEQ ID NO:586 Ｈ Polypeptide and V of SEQ ID NO:588 Ｌ those containing polypeptides, (l) V of SEQ ID NO: 596 Ｈ Polypeptide and V of SEQ ID NO:598 Ｌ those containing polypeptides, (li) V of SEQ ID NO: 606 Ｈ Polypeptide and V of SEQ ID NO:608 Ｌ those containing polypeptides, (lii) V of SEQ ID NO: 616 Ｈ Polypeptide and V of SEQ ID NO:618 Ｌ those containing polypeptides, (liii) V of SEQ ID NO: 626 Ｈ Polypeptides and V of SEQ ID NO:628 Ｌ those containing polypeptides, (liv) V of SEQ ID NO: 636 Ｈ Polypeptide and V of SEQ ID NO:638 Ｌ those containing polypeptides, (lv) V of SEQ ID NO: 646 Ｈ Polypeptides and V of SEQ ID NO:648 Ｌ those containing polypeptides, (lvi) V of SEQ ID NO: 656 Ｈ Polypeptide and V of SEQ ID NO:658 Ｌ those containing polypeptides, (lvii) V of SEQ ID NO: 666 Ｈ Polypeptide and V of SEQ ID NO:668 Ｌ those containing polypeptides, (lviii) V of SEQ ID NO: 676 Ｈ Polypeptide and V of SEQ ID NO:678 Ｌ those containing polypeptides, (lix) V of SEQ ID NO: 686 Ｈ Polypeptide and V of SEQ ID NO:688 Ｌ those containing polypeptides, (lx) V of SEQ ID NO: 696 Ｈ Polypeptide and V of SEQ ID NO:698 Ｌ those containing polypeptides, (lxi) V of SEQ ID NO: 706 Ｈ Polypeptide and V of SEQ ID NO:708 Ｌ those containing polypeptides, (lxii) V of SEQ ID NO: 716 Ｈ Polypeptide and V of SEQ ID NO:718 Ｌ those containing polypeptides, (lxiii) V of SEQ ID NO: 726 Ｈ Polypeptide and V of SEQ ID NO:728 Ｌ those containing polypeptides, (lxiv) V of SEQ ID NO:736 Ｈ Polypeptide and V of SEQ ID NO:738 Ｌ those containing polypeptides, (lxv) V of SEQ ID NO:746 Ｈ Polypeptide and V of SEQ ID NO:748 Ｌ those containing polypeptides, (lxvi) V of SEQ ID NO:756 Ｈ Polypeptide and V of SEQ ID NO:758 Ｌ those containing polypeptides, (lxvii) V of SEQ ID NO: 766 Ｈ Polypeptide and V of SEQ ID NO:768 Ｌ those containing polypeptides, (lxviii) V of SEQ ID NO: 776 Ｈ Polypeptide and V of SEQ ID NO:778 Ｌ those containing polypeptides, (lxix) V of SEQ ID NO:786 Ｈ Polypeptide and V of SEQ ID NO:788 Ｌ those containing polypeptides, (lxx) V of SEQ ID NO:796 Ｈ Polypeptide and V of SEQ ID NO:798 Ｌ those containing polypeptides, (lxxi) V of SEQ ID NO: 806 Ｈ Polypeptide and V of SEQ ID NO:808 Ｌ those containing polypeptides, and (lxxii) V of SEQ ID NO: 816 Ｈ Polypeptide and V of SEQ ID NO:818 Ｌ 87. The antibody drug conjugate (ADC), agent or composition of any one of claims 13-17, 25-26, 30-39 and 41-86, which shares at least 90%, 95%, or 100% sequence identity with said antibody, including sequences of those comprising a polypeptide, and further wherein said CDRs are unmodified.

88. 88. The antibody drug conjugate (ADC), agent or composition of any one of claims 13-17, 25-26, 30-39 and 41-87, wherein the ADC comprises an anti-human VISTA antibody or antibody fragment, and the anti-VISTA antibody or antibody fragment comprises the same variable region as one of VSTB92, VSTB56, VSTB95, VSTB103, and VSTB66.

89. 90. The antibody drug conjugate (ADC), agent or composition of any one of claims 13-17, 25-26, 30-39 and 41-88, wherein the ADC comprises an anti-human VISTA antibody or antibody fragment, the anti-VISTA antibody or antibody fragment comprising a human IgG2 kappa backbone with V234A / G237A / P238S / H268A / V309L / A330S / P331S silencing mutations in the Fc region.

90. 90. The antibody drug conjugate (ADC), agent or composition of any one of claims 13-17, 25-26, 30-39 and 41-89, wherein the ADC comprises an anti-human VISTA antibody or antibody fragment, the anti-VISTA antibody or antibody fragment comprising a human IgG1 / kappa backbone with L234A / L235A silencing mutations in the Fc region.

91. 100. The ADC, agent or composition of any one of claims 13-17, 25-26, 30-39 and 41-90, wherein the glucocorticosteroid agonist or linker conjugate is conjugated to an antibody or antibody fragment, optionally an anti-human VISTA antibody or antibody fragment, via its interchain disulfide.

92. A pharmaceutical composition comprising a therapeutically effective amount of at least one antibody drug conjugate (ADC) or a steroid agonist or a steroid linker according to any one of claims 1 to 31 and 52 to 91, and a pharma- ceutically acceptable carrier.

93. 93. The composition of claim 92, optionally administrable via intravenous, intramuscular, intrathecal, or subcutaneous injection routes.

94. 94. The composition of claim 92 or 93, which is administerable subcutaneously.

95. 95. A device comprising the glucocorticosteroid agonist, linker conjugate, ADC, composition, or agent of any one of claims 1-39 and 41-94, providing subcutaneous administration selected from the group consisting of a syringe, an injection device, an infusion pump, an injector pen, a needle-free device, an auto-injector, and a subcutaneous patch delivery system.

96. 96. The device of claim 95, which delivers a fixed dose of the glucocorticoid receptor agonist or functional derivative thereof to a patient.

97. 97. A kit comprising the device of claim 95 or 96, further comprising instructions informing the patient of the method and dosing regimen of administering the ADC composition contained therein.

98. A medicament comprising at least one antibody drug conjugate (ADC) or a steroid or a composition according to any one of claims 1 to 39 and 52 to 94 for treatment and / or prevention, said composition may be present in a device according to any one of claims 95 to 96.

99. 99. The method of claim 98, for use in treating allergy, autoimmunity, transplantation, gene therapy, inflammation, GVHD, or sepsis in a human subject, or for treating or preventing inflammatory, autoimmune, or allergic side effects associated with any of the foregoing conditions.

100. 100. The method of claim 98 or 99, wherein the inflammation is associated with cancer or an infectious disease, optionally a viral or bacterial infection.

101. 100. The method of claim 98 or 99, wherein the patient has a condition selected from rheumatoid arthritis, juvenile idiopathic arthritis, psoriatic arthritis, ankylosing spondylitis, adult Crohn's disease, pediatric Crohn's disease, ulcerative colitis, plaque psoriasis, hidradenitis suppurativa, uveitis, Behcet's disease, spondyloarthropathy, or psoriasis.

102. The patient has one or more of the following: (i) chronic, acute, or episodic allergic, inflammatory, or inflammatory conditions, e.g., chronic, acute, episodic, remitting / relapsing; (ii) conditions that are only primarily treatable effectively with high doses of steroids, optionally polymyalgia rheumatica and / or giant cell arteritis, where the patient is optionally being treated or being treated with high doses of steroids; (iii) conditions with comorbidities limiting steroid use, optionally diabetes mellitus, non-alcoholic steatohepatitis (NASH), morbid obesity, avascular / osteonecrosis (AVN), glaucoma, steroid-induced hypertension, severe skin fragility, and / or osteoarthritis; (iv) AAV, polymyositis, dermatomyositis, lupus, inflammatory lung disease, autoimmune hepatitis, inflammatory bowel disease, immune thrombocytopenia, autoimmune hemolytic anemia, gout patients in conditions where safe long-term treatments are available but induction with high doses of steroids for several months is desirable, optionally where induction with high doses of steroids for several months is therapeutically justified; (v) Skin conditions requiring short / long term treatment, optionally conditions of uncertain treatment or duration and / or conditions with no effective alternative to steroid administration, optionally other severe immune-related skin conditions such as Stevens-Johnson, other severe drug rash conditions, conditions with widespread contact dermatitis, PG, LCV, erythroderma, and the like; (vi) conditions treated with high dose corticosteroids for exacerbations / recurrences, optionally COPD, asthma, lupus, gout, pseudogout, (vii) immune-related neurological disorders such as small fiber neuropathy, MS (subset), chronic inflammatory demyelinating polyneuropathy, myasthenia gravis, and the like; (viii) optionally hematology / oncology indications where high doses of steroids are therapeutically justified or beneficial; (ix) an ophthalmic condition, optionally uveitis, iritis, scleritis, and the like; (x) conditions associated with permanent or very long-term adrenal insufficiency or secondary adrenal insufficiency, optionally, iatrogenic Addisonian crisis; (xi) conditions that are often treated with long-term low-dose steroids, optionally lupus, RA, psA, vasculitis, and the like; and (xii) The medicament according to any one of claims 98 to 101, including special classes of patients such as pregnant / lactating women, pediatric patients, optionally with growth disorders or cataracts.

103. The method according to any one of claims 98 to 102, wherein the patient is further treated with another active agent.

104. 104. The agent of any one of claims 98 to 103, wherein the patient is further treated with an immunomodulatory antibody or fusion protein selected from an immunoinhibitory antibody or fusion protein targeting one or more of CTLA4, PD-1, PDL-1, LAG-3, TIM-3, BTLA, B7-H4, B7-H3, VISTA, and / or an agonistic antibody or fusion protein targeting one or more of CD40, CD137, OX40, GITR, CD27, CD28, or ICOS.

105. A drug for ex vivo use comprising an ADC or steroid as defined in any one of claims 1 to 31 and 52 to 91, wherein immune cells from a patient or donor are contacted with the ADC or steroid as defined in any one of claims 1 to 31 and 52 to 91 and then injected into a patient in need thereof, for example a patient having one or more of the conditions identified in claims 42 to 51 and 99 to 104.

106. 13. The ADC of any one of claims 13-17, 25-26, 30-31 and 52-91, wherein the linker is a positively, negatively or neutrally charged cleavable peptide, which is optionally esterase cleavable.

107. 107. The ADC of any one of claims 13-17, 25-26, 30-31, 52-91 and 106, wherein the drug-antibody ratio is in the range of 1-12:1 or 1-10:

1.

108. 20. The ADC of claim 13, wherein the drug to antibody ratio is in the range of 2-8:1, 4-8:1, or 6-8:

1.

109. 109. The ADC of any one of claims 13-17, 25-26, 30-31, 52-91, and 106-108, wherein the drug to antibody ratio is 4:1 (n=4), 6:1 (n=6), 8:1 (n=8), 10:1 (n=10), 12:1 (n=12), or n is 12 or more and in the range of 12 to 50.

110. The ADC of any one of claims 13-17, 25-26, 30-31, 52-91 and 106-109, which internalizes one or more of activated or non-activated monocytes, myeloid cells, B cells, NK cells, T cells, CD4 T cells, CD8 T cells, Tregs, eosinophils, dendritic cells, mast cells, macrophages, and neutrophils.

111. The ADC of any one of claims 13 to 17, 25 to 26, 30 to 31, 52 to 91 and 106 to 110, which does not appreciably internalize activated or non-activated B cells.

112. 17. The ADC of any one of claims 13-17, 25-26, 30-31, 52-91 and 106-111, which, when administered to a subject in need of treatment, promotes efficacy and / or reduces adverse side effects associated with said glucocorticoid receptor agonist as compared to the same dose of an anti-inflammatory agent administered in naked (unconjugated) form.

113. 13. The antibody drug conjugate (ADC) of any one of claims 13-17, 25-26, 30-31, 52-91 and 106-112, wherein the glucocorticoid receptor agonist is conjugated to the antibody or antigen-binding fragment via the interchain disulfide.

114. 13. The antibody drug conjugate (ADC) of any one of claims 13 to 17, 25 to 26, 30 to 31, 52 to 91 and 106 to 113, comprising an esterase-sensitive linker.

115. The antibody drug conjugate (ADC) of any one of claims 13-17, 25-26, 30-31, 52-91 and 106-114, wherein the cleavable linker is susceptible to one or more of acid-induced cleavage, photo-induced cleavage, peptidase-induced cleavage, esterase-induced cleavage, and disulfide bond cleavage.

116. 17. The antibody drug conjugate (ADC) of any one of claims 13-17, 25-26, 30-31, 52-91 and 106-115, comprising a non-cleavable linker that is substantially resistant to one or more of acid-induced cleavage, photo-induced cleavage, peptidase-induced cleavage, esterase-induced cleavage, and disulfide bond cleavage.

117. 17. The antibody drug conjugate (ADC) of any one of claims 13-17, 25-26, 30-31, 52-91 and 106-116, wherein the anti-VISTA antigen-binding fragment comprised in the ADC comprises a Fab, F(ab')2, or scFv antibody fragment.

118. A medicament comprising at least one antibody drug conjugate (ADC) or composition for treatment and / or prevention, said composition may be present in a device according to any one of claims 40 and 95 to 96.

119. The agent described in claim 118, for use in treating allergy, autoimmunity, transplantation, gene therapy, inflammation, GVHD, or sepsis in a human subject, or for treating or preventing inflammatory, autoimmune, or allergic side effects associated with any of the aforementioned conditions.

120. The method of claim 118 or 119, wherein the patient has a condition selected from rheumatoid arthritis, juvenile idiopathic arthritis, psoriatic arthritis, ankylosing spondylitis, adult Crohn's disease, pediatric Crohn's disease, ulcerative colitis, plaque psoriasis, hidradenitis suppurativa, uveitis, Behcet's disease, spondyloarthropathy, or psoriasis.

121. The patient has one or more of the following: (i) conditions which are only primarily treatable effectively with high doses of steroids, optionally polymyalgia rheumatica and / or giant cell arteritis, where the patient is optionally being treated or being treated with high doses of steroids; (ii) conditions with comorbidities limiting steroid use, optionally diabetes mellitus, non-alcoholic steatohepatitis (NASH), morbid obesity, avascular / osteonecrosis (AVN), glaucoma, steroid-induced hypertension, severe skin fragility, and / or osteoarthritis; (iii) AAV, polymyositis, dermatomyositis, lupus, inflammatory lung disease, autoimmune hepatitis, inflammatory bowel disease, immune thrombocytopenia, autoimmune hemolytic anemia, gout patients in conditions where safe long-term treatments are available but induction with high doses of steroids for several months is desirable, optionally where induction with high doses of steroids for several months is therapeutically justified; (iv) Skin conditions requiring short / long term treatment, optionally conditions of uncertain treatment or duration and / or conditions with no effective alternative to steroid administration, optionally other severe immune-related skin conditions such as Stevens-Johnson, other severe drug rash conditions, conditions with widespread contact dermatitis, PG, LCV, erythroderma, and the like; (v) conditions treated with high dose corticosteroids for exacerbations / recurrences, optionally COPD, asthma, lupus, gout, pseudogout, (vi) immune-related neurological disorders such as small fiber neuropathy, MS (subset), chronic inflammatory demyelinating polyneuropathy, myasthenia gravis, and the like; (vii) optionally, hematology / oncology indications where high doses of steroids are therapeutically justified or beneficial; (viii) ophthalmic conditions, optionally uveitis, iritis, scleritis, and the like; (ix) conditions associated with permanent or very long-term adrenal insufficiency or secondary adrenal insufficiency, optionally iatrogenic Addisonian crisis; (x) conditions that are often treated with long-term low-dose steroids, optionally lupus, RA, psA, vasculitis, and the like; and (xi) The medicament according to any one of claims 118 to 120, including special classes of patients such as pregnant / lactating women, pediatric patients, optionally with growth disorders or cataracts.

122. The method according to any one of claims 118 to 121, wherein the patient is further treated with another active agent.

123. The agent of any one of claims 118 to 122, wherein the patient is further treated with an immunomodulatory antibody or fusion protein selected from an immunoinhibitory antibody or fusion protein targeting one or more of CTLA4, PD-1, PDL-1, LAG-3, TIM-3, BTLA, B7-H4, B7-H3, VISTA, and / or an agonistic antibody or fusion protein targeting one or more of CD40, CD137, OX40, GITR, CD27, CD28, or ICOS.

124. 124. A medicament according to any one of claims 118 to 123 for the treatment or prevention of acute or chronic inflammation and autoimmune and inflammatory indications associated therewith, said conditions optionally including severe asthma, giant cell arteritis, ANKA vasculitis, and IBD (colitis and Crohn's disease).

125. 125. The method of any one of claims 118 to 124, for the treatment or prevention of a condition selected from rheumatoid arthritis, juvenile idiopathic arthritis, psoriatic arthritis, ankylosing spondylitis, adult Crohn's disease, pediatric Crohn's disease, ulcerative colitis, plaque psoriasis, hidradenitis suppurativa, uveitis, Behcet's disease, spondyloarthropathy, or psoriasis.

126. 13. A medicament comprising an ADC of any one of claims 13-17, 25-26, 30-31, 52-91 and 106-117 for effecting internalization of a glucocorticosteroid into one or more of T cells, CD4 T cells, CD8 T cells, Tregs, NK cells, B cells, neutrophils, monocytes, myeloid cells, dendritic cells, eosinophils, mast cells, and macrophages, comprising administering to a subject or contacting therewith a cell obtained from a subject ex vivo.

127. The agent of claim 126, wherein the immune cell-containing purified or enriched composition is contacted ex vivo with the ADC of any one of claims 13-17, 25-26, 30-31, 52-91 and 106-117 and then introduced into a patient in need thereof, the immune cell-containing purified or enriched composition being achieved ex vivo and comprising immune cells or one or more specific types of immune cells selected from B cells, T cells, CD4 T cells, CD8 T cells, Tregs, NK cells, neutrophils, monocytes, myeloid cells, dendritic cells, eosinophils, mast cells, and macrophages.

128. 18. A medicament comprising the ADC of any one of claims 13-17, 25-26, 30-31, 52-91 and 106-117 for treating an inflammatory, autoimmune, or allergic condition involving any one or more of B cells, T cells, Tregs, NK cells, neutrophils, monocytes, myeloid cells, dendritic cells, eosinophils, mast cells, and macrophages.

129. 129. A glucocorticoid agonist, composition containing, or medicament according to any one of claims 1 to 128, which does not have the following formula: 【Chemical 36】

130. The glucocorticoid agonist compound does not consist of a compound having the structure: 【Chemical 37】 During the ceremony, R=H, or R = 【Chemical Formula 38】 or R = 【Chemical Formula 39】 or R = 【Chemistry 40】 or R = 【Chemistry 41】 or R = 【Chemistry 42】 or R = 【Chemistry 43】 or R = 【Chemistry 44】 The glucocorticoid agonist, composition containing it, or medicament according to any one of claims 1 to 129,

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